4-83485066-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ABRAXAS1
NM_139076.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.41

Publications

1 publications found

Variant links:

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]

ABRAXAS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 VariationId is 416705.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000209

AC:

AN:

225418

AF XY:

0.000153

show subpopulations

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 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.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

714592

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30472

American (AMR)

AF:

0.000352

AC:

AN:

42660

Ashkenazi Jewish (ASJ)

AF:

0.0000395

AC:

AN:

25324

East Asian (EAS)

AF:

0.000244

AC:

AN:

36938

South Asian (SAS)

AF:

0.000156

AC:

AN:

83580

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000746

AC:

AN:

1099684

Other (OTH)

AF:

0.000457

AC:

AN:

59124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41584

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000288

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.000174

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign: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

Apr 02, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7G>C (p.G3R) alteration is located in exon 1 (coding exon 1) of the FAM175A gene. This alteration results from a G to C substitution at nucleotide position 7, causing the glycine (G) at amino acid position 3 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, 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

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0045

T;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

.;.

PhyloP100

2.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.79

N;.

REVEL

Benign

0.20

Sift

Uncertain

0.013

D;.

Sift4G

Uncertain

0.020

D;D

Vest4

0.41

ClinPred

0.025

GERP RS

3.3

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.46

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over