rs769383568

Variant names:

• chr4-83467459-A-G
• rs769383568
• NM_139076.3:c.676T>C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_139076.3(ABRAXAS1):​c.676T>C​(p.Leu226Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,503,310 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: ABRAXAS1 NM_139076.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.52

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]

MRPS18C (HGNC:16633): (mitochondrial ribosomal protein S18C) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S18P family. The encoded protein is one of three that has significant sequence similarity to bacterial S18 proteins. The primary sequences of the three human mitochondrial S18 proteins are no more closely related to each other than they are to the prokaryotic S18 proteins. Pseudogenes corresponding to this gene are found on chromosomes 8p, 12p, 15q, and 22q. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-83467459-A-G is Benign according to our data. Variant chr4-83467459-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 241857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABRAXAS1	NM_139076.3	c.676T>C	p.Leu226Leu	synonymous_variant	Exon 7 of 9	ENST00000321945.12	NP_620775.2
ABRAXAS1	NM_001345962.2	c.349T>C	p.Leu117Leu	synonymous_variant	Exon 6 of 8		NP_001332891.1
ABRAXAS1	XR_001741334.3	n.704T>C		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.676T>C	p.Leu226Leu	synonymous_variant	Exon 7 of 9	1	NM_139076.3	ENSP00000369857.3
ABRAXAS1	ENST00000611288.4	c.331T>C	p.Leu111Leu	synonymous_variant	Exon 3 of 5	5		ENSP00000482434.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000690 AC: 17 AN: 246434 Hom.: 0 AF XY: 0.0000526 AC XY: 7 AN XY: 133200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 50 AN: 1351098 Hom.: 0 Cov.: 21 AF XY: 0.0000325 AC XY: 22 AN XY: 677254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000461

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000769

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000404

Gnomad4 OTH exome AF: 0.0000353

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 12, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 12, 2017

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.676T>C (p.Leu226Leu) variant involves the alteration of a conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may slightly alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 21/272520 control chromosomes at a frequency of 0.0000771, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic FAM175A variant (0.0000313), suggesting this variant is likely a benign polymorphism. A clinical diagnostic laboratory classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -

not provided Benign:1

May 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.7
DANN	Benign	0.85

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: rs769383568; hg19: chr4-84388612;