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). Synonymous variant affecting the same amino acid position (i.e. Q122Q) has been classified as Likely benign.

• 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;