4-83462582-C-T

Variant names:

• chr4-83462582-C-T
• rs13125836
• NM_139076.3:c.1117G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139076.3(ABRAXAS1):​c.1117G>A​(p.Asp373Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,614,020 control chromosomes in the GnomAD database, including 2,409 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D373G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (192 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2217 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.30
• Publications: 25 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025427938).
• BP6: Variant 4-83462582-C-T is Benign according to our data. Variant chr4-83462582-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139076.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABRAXAS1	NM_139076.3	MANE Select	c.1117G>A	p.Asp373Asn	missense	Exon 9 of 9	NP_620775.2	Q6UWZ7-1
	ABRAXAS1	NM_001345962.2		c.790G>A	p.Asp264Asn	missense	Exon 8 of 8	NP_001332891.1	Q6UWZ7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABRAXAS1	ENST00000321945.12	TSL:1 MANE Select	c.1117G>A	p.Asp373Asn	missense	Exon 9 of 9	ENSP00000369857.3	Q6UWZ7-1
	ABRAXAS1	ENST00000856950.1		c.1105G>A	p.Asp369Asn	missense	Exon 9 of 9	ENSP00000527009.1
	ABRAXAS1	ENST00000856949.1		c.997G>A	p.Asp333Asn	missense	Exon 8 of 8	ENSP00000527008.1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6382 AN: 152136 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0456

Gnomad ASJ AF: 0.0901

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0968

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0542

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0440 AC: 11060 AN: 251372 AF XY: 0.0446

Gnomad AFR exome AF: 0.00954

Gnomad AMR exome AF: 0.0330

Gnomad ASJ exome AF: 0.0836

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0893

Gnomad NFE exome AF: 0.0556

Gnomad OTH exome AF: 0.0587

GnomAD4 exome AF: 0.0513 AC: 75042 AN: 1461766 Hom.: 2217 Cov.: 31 AF XY: 0.0506 AC XY: 36760 AN XY: 727188

African (AFR) AF: 0.00833 AC: 279 AN: 33476

American (AMR) AF: 0.0345 AC: 1541 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 2341 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.0110 AC: 946 AN: 86254

European-Finnish (FIN) AF: 0.0839 AC: 4482 AN: 53416

Middle Eastern (MID) AF: 0.0690 AC: 398 AN: 5766

European-Non Finnish (NFE) AF: 0.0560 AC: 62283 AN: 1111936

Other (OTH) AF: 0.0459 AC: 2771 AN: 60388

GnomAD4 genome AF: 0.0419 AC: 6377 AN: 152254 Hom.: 192 Cov.: 33 AF XY: 0.0433 AC XY: 3220 AN XY: 74428

African (AFR) AF: 0.0104 AC: 432 AN: 41564

American (AMR) AF: 0.0456 AC: 696 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0901 AC: 313 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4828

European-Finnish (FIN) AF: 0.0968 AC: 1026 AN: 10594

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0542 AC: 3687 AN: 68020

Other (OTH) AF: 0.0478 AC: 101 AN: 2112

Alfa AF: 0.0516 Hom.: 689

Bravo AF: 0.0387

TwinsUK AF: 0.0485 AC: 180

ALSPAC AF: 0.0509 AC: 196

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0536 AC: 461

ExAC AF: 0.0424 AC: 5152

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0629

EpiControl AF: 0.0624

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ABRAXAS1-related disorder (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0040	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Benign	0.097	T
Sift4G	Benign	0.071	T
Polyphen		0.99	D
Vest4		0.12
MPC		0.40
ClinPred		0.0096	T
GERP RS		5.1
Varity_R		0.093
gMVP		0.15
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13125836; hg19: chr4-84383735; COSMIC: COSV55030274;