NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002513130.1

Allele description

NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)

Gene:

MTPAP:mitochondrial poly(A) polymerase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10p11.23

Genomic location:

Preferred name:

NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)

HGVS:

NC_000010.11:g.30313926T>C
NG_028096.1:g.40413A>G
NM_018109.4:c.1432A>GMANE SELECT
NP_060579.3:p.Asn478Asp
NC_000010.10:g.30602855T>C
Q9NVV4:p.Asn478Asp

Protein change:

N478D; ASN478ASP

Links:

UniProtKB: Q9NVV4#VAR_064907; OMIM: 613669.0001; dbSNP: rs267606900

NCBI 1000 Genomes Browser:

rs267606900

Molecular consequence:

NM_018109.4:c.1432A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003441423	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20970105, 24651433, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003441423

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 22, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Defective mitochondrial mRNA maturation is associated with spastic ataxia.

Crosby AH, Patel H, Chioza BA, Proukakis C, Gurtz K, Patton MA, Sharifi R, Harlalka G, Simpson MA, Dick K, Reed JA, Al-Memar A, Chrzanowska-Lightowlers ZM, Cross HE, Lightowlers RN.

Am J Hum Genet. 2010 Nov 12;87(5):655-60. doi: 10.1016/j.ajhg.2010.09.013. Epub 2010 Oct 21.

PubMed [citation]

PMID:: 20970105
PMCID:: PMC2978972

Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks.

Martin NT, Nakamura K, Paila U, Woo J, Brown C, Wright JA, Teraoka SN, Haghayegh S, McCurdy D, Schneider M, Hu H, Quinlan AR, Gatti RA, Concannon P.

Cell Death Dis. 2014 Mar 20;5:e1130. doi: 10.1038/cddis.2014.99.

PubMed [citation]

PMID:: 24651433
PMCID:: PMC3973239

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003441423.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 478 of the MTPAP protein (p.Asn478Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with spastic ataxia (PMID: 20970105, 24651433). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18391). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MTPAP protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 7, 2023

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