NM_139076.3:c.7G>C

Variant names:

• chr4-83485066-C-G
• rs370520589
• NM_139076.3:c.7G>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_139076.3(ABRAXAS1):​c.7G>C​(p.Gly3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,588,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.41

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03788981).
• BP6: Variant 4-83485066-C-G is Benign according to our data. Variant chr4-83485066-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 416705.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABRAXAS1	NM_139076.3	c.7G>C	p.Gly3Arg	missense_variant	Exon 1 of 9	ENST00000321945.12	NP_620775.2
ABRAXAS1	NM_001345962.2	c.-254G>C		5_prime_UTR_variant	Exon 1 of 8		NP_001332891.1
ABRAXAS1	XR_001741334.3	n.35G>C		non_coding_transcript_exon_variant	Exon 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.7G>C	p.Gly3Arg	missense_variant	Exon 1 of 9	1	NM_139076.3	ENSP00000369857.3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000209 AC: 47 AN: 225418 Hom.: 0 AF XY: 0.000153 AC XY: 19 AN XY: 124266

Gnomad AFR exome AF: 0.000175

Gnomad AMR exome AF: 0.000412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.000213

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000582

Gnomad OTH exome AF: 0.000374

GnomAD4 exome AF: 0.000104 AC: 149 AN: 1435804 Hom.: 0 Cov.: 30 AF XY: 0.000106 AC XY: 76 AN XY: 714592

Gnomad4 AFR exome AF: 0.0000328

Gnomad4 AMR exome AF: 0.000352

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.000244

Gnomad4 SAS exome AF: 0.000156

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.000457

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74470

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000444 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.000174 AC: 21

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Nov 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FAM175A c.7G>C (p.Gly3Arg) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 21/110618 (1/5268), predominantly in the East Asian cohort, 11/8310 (1/755), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic FAM175A variant of 1/31948. Therefore, suggesting the variant is a common polymorphism found in population(s) of East Asian origin. The variant of interest, to our knowledge, has not been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, the variant of interest has been classified as Benign. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABRAXAS1 p.Gly3Arg variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs370520589) and ClinVar (classified as benign by Integrated Genetics and as likely benign by Invitae). The variant was identified in control databases in 45 of 244124 chromosomes at a frequency of 0.0001843 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: East Asian in 14 of 15954 chromosomes (freq: 0.000878), Latino in 13 of 32124 chromosomes (freq: 0.000405), Other in 2 of 5956 chromosomes (freq: 0.000336), South Asian in 6 of 28140 chromosomes (freq: 0.000213), African in 3 of 18920 chromosomes (freq: 0.000159) and European (non-Finnish) in 7 of 109034 chromosomes (freq: 0.000064), but was not observed in the Ashkenazi Jewish, or European (Finnish) populations. The p.Gly3 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Uncertain:1

Sep 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G3R variant (also known as c.7G>C), located in coding exon 1 of the FAM175A gene, results from a G to C substitution at nucleotide position 7. The glycine at codon 3 is replaced by arginine, an amino acid with dissimilar 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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0045	T;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-0.86	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.79	N;.
REVEL	Benign	0.20
Sift	Uncertain	0.013	D;.
Sift4G	Uncertain	0.020	D;D
Polyphen		0.98	D;.
Vest4		0.41
MutPred		0.14		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.35
MPC		0.53
ClinPred		0.025	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs370520589; hg19: chr4-84406219;