4-83470315-G-C

Variant names:

• chr4-83470315-G-C
• rs137876115
• NM_139076.3:c.364C>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.364C>G​(p.Gln122Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,613,826 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.46

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=0.005658865).
• BP6: Variant 4-83470315-G-C is Benign according to our data. Variant chr4-83470315-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128220.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.364C>G	p.Gln122Glu	missense_variant	Exon 5 of 9	ENST00000321945.12	NP_620775.2
ABRAXAS1	NM_001345962.2	c.37C>G	p.Gln13Glu	missense_variant	Exon 4 of 8		NP_001332891.1
ABRAXAS1	XR_001741334.3	n.392C>G		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.364C>G	p.Gln122Glu	missense_variant	Exon 5 of 9	1	NM_139076.3	ENSP00000369857.3
ABRAXAS1	ENST00000611288.4	c.19C>G	p.Gln7Glu	missense_variant	Exon 1 of 5	5		ENSP00000482434.1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000402 AC: 101 AN: 251138 Hom.: 0 AF XY: 0.000317 AC XY: 43 AN XY: 135742

Gnomad AFR exome AF: 0.00585

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 99 AN XY: 727094

Gnomad4 AFR exome AF: 0.00580

Gnomad4 AMR exome AF: 0.000246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74452

Gnomad4 AFR AF: 0.00515

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00160

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FAM175A has only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted FAM175A c.364C>G at the cDNA level, p.Gln122Glu (Q122E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FAM175A Gln122Glu was observed with an allele frequency of 0.2% in Africans in 1000 Genomes and 0.7% in African Americans in the NHLBI Exome Sequencing Project. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution and may affect secondary protein structure. FAM175A Gln122Glu occurs at a position that is highly conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or 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 16, 2017

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.364C>G (p.Gln122Glu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 56/123538 control chromosomes at a frequency of 0.0004533, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic FAM175A variant (0.0000313), suggesting this variant is likely a benign polymorphism. This variant has been reported in three patients with early onset breast cancer without strong evidence supporting its pathogenicity (Renault_2016). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.0053	T;.;T;.;.
Eigen	Benign	0.096
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0057	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.060	T;D;.;.;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.88	P;.;.;.;.
Vest4		0.30
MVP		0.22
MPC		0.20
ClinPred		0.045	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137876115; hg19: chr4-84391468;