4-83463514-C-T

Variant names:

• chr4-83463514-C-T
• NM_139076.3:c.776G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139076.3(ABRAXAS1):​c.776G>A​(p.Gly259Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.643

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040904403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABRAXAS1	NM_139076.3	c.776G>A	p.Gly259Glu	missense_variant	Exon 8 of 9	ENST00000321945.12	NP_620775.2
ABRAXAS1	NM_001345962.2	c.449G>A	p.Gly150Glu	missense_variant	Exon 7 of 8		NP_001332891.1
ABRAXAS1	XR_001741334.3	n.*7G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.776G>A	p.Gly259Glu	missense_variant	Exon 8 of 9	1	NM_139076.3	ENSP00000369857.3
ABRAXAS1	ENST00000611288.4	c.*267G>A		downstream_gene_variant		5		ENSP00000482434.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.87e-7 AC: 1 AN: 1455762 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G259E variant (also known as c.776G>A), located in coding exon 8 of the FAM175A gene, results from a G to A substitution at nucleotide position 776. The glycine at codon 259 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.7
DANN	Benign	0.52
DEOGEN2	Benign	0.00081	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.19	T
PROVEAN	Benign	2.1	N;N
REVEL	Benign	0.026
Sift	Benign	0.30	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.20		Gain of helix (P = 0.0325);.;
MVP		0.061
MPC		0.13
ClinPred		0.10	T
GERP RS		-1.8
Varity_R		0.045
gMVP		0.13

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-84384667;