rs201948472

Variant names:

• chr4-83482207-T-C
• rs201948472
• NM_139076.3:c.125A>G

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.125A>G​(p.Lys42Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000298 in 1,612,592 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 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.85

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=0.03453189).
• BP6: Variant 4-83482207-T-C is Benign according to our data. Variant chr4-83482207-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128218.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABRAXAS1	NM_139076.3	c.125A>G	p.Lys42Arg	missense_variant	Exon 2 of 9	ENST00000321945.12	NP_620775.2
ABRAXAS1	NM_001345962.2	c.-136A>G		5_prime_UTR_variant	Exon 2 of 8		NP_001332891.1
ABRAXAS1	XR_001741334.3	n.153A>G		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.125A>G	p.Lys42Arg	missense_variant	Exon 2 of 9	1	NM_139076.3	ENSP00000369857.3

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000303 AC: 75 AN: 247884 Hom.: 0 AF XY: 0.000253 AC XY: 34 AN XY: 134584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000301 AC: 440 AN: 1460356 Hom.: 0 Cov.: 29 AF XY: 0.000299 AC XY: 217 AN XY: 726526

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000899

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000541 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000224 AC: 27

EpiCase AF: 0.000983

EpiControl AF: 0.000534

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

Jan 23, 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.125A>G at the cDNA level, p.Lys42Arg (K42R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FAM175A Lys42Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one positive polar amino acid for another, altering a position that is well conserved throughout evolution and is located in within the MPN-like domain. In silico analyses are inconsistent with regard to the effect this variant may have 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 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FAM175A c.125A>G (p.Lys42Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 28/122744 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0011211 (1/892). This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic FAM175A variant (0.0000313), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in one BrC pt without strong evidence for causality. In addition, one clinical diagnostic lab classified this variant as uncertain significance, without evidence to independently evaluate. Taken together, this variant is classified as likely benign unitl more evidence becomes available. -

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	0.099
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0029	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Benign	0.081
Sift	Benign	0.17	T;.;.
Sift4G	Benign	0.21	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.36
MVP		0.38
MPC		0.15
ClinPred		0.12	T
GERP RS		4.3
Varity_R		0.060
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: rs201948472; hg19: chr4-84403360;