4-83462591-A-T

Variant names:

• chr4-83462591-A-T
• rs587780263
• NM_139076.3:c.1108T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139076.3(ABRAXAS1):​c.1108T>A​(p.Ser370Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S370A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.297
• Publications: 1 publications found

Genes affected

ABRAXAS1 (HGNC:25829): (abraxas 1, BRCA1 A complex subunit) This gene encodes a protein that binds to the C-terminal repeats of breast cancer 1 (BRCA1) through a phospho-SXXF motif. The encoded protein recruits ubiquitin interaction motif containing 1 protein to BRCA1 protein and is required for DNA damage resistance, DNA repair, and cell cycle checkpoint control. Pseudogenes of this gene are found on chromosomes 3 and 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

MRPS18C (HGNC:16633): (mitochondrial ribosomal protein S18C) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S18P family. The encoded protein is one of three that has significant sequence similarity to bacterial S18 proteins. The primary sequences of the three human mitochondrial S18 proteins are no more closely related to each other than they are to the prokaryotic S18 proteins. Pseudogenes corresponding to this gene are found on chromosomes 8p, 12p, 15q, and 22q. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06686565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABRAXAS1	NM_139076.3	c.1108T>A	p.Ser370Thr	missense_variant	Exon 9 of 9	ENST00000321945.12	NP_620775.2
ABRAXAS1	NM_001345962.2	c.781T>A	p.Ser261Thr	missense_variant	Exon 8 of 8		NP_001332891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.1108T>A	p.Ser370Thr	missense_variant	Exon 9 of 9	1	NM_139076.3	ENSP00000369857.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251356 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Feb 24, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FAM175A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted FAM175A c.1108T>A at the cDNA level, p.Ser370Thr (S370T) at the protein level, and results in the change of a Serine to a Threonine (TCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FAM175A Ser370Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral polar amino acid for another, altering a position that is highly variable throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the FAM175A gene, remain unclear. -

Jan 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 128216). This variant has not been reported in the literature in individuals affected with ABRAXAS1-related conditions. This variant is present in population databases (rs587780263, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 370 of the ABRAXAS1 protein (p.Ser370Thr). -

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.1
DANN	Benign	0.78
DEOGEN2	Benign	0.0035	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.38	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.30
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.084
Sift	Benign	0.41	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.20	B;.
Vest4		0.042
MutPred		0.13		Gain of glycosylation at T365 (P = 0.0087);.;
MVP		0.35
MPC		0.11
ClinPred		0.16	T
GERP RS		3.8
Varity_R		0.057
gMVP		0.17
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780263; hg19: chr4-84383744;