4-83462657-C-T

Variant names:

• chr4-83462657-C-T
• rs12642536
• NM_139076.3:c.1042G>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.1042G>A​(p.Ala348Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,613,528 control chromosomes in the GnomAD database, including 142,799 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A348S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (11400 hom., cov: 32)
  • Exomes 𝑓: 0.42 (131399 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.560
• Publications: 43 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=3.806956E-6).
• BP6: Variant 4-83462657-C-T is Benign according to our data. Variant chr4-83462657-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 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.1042G>A	p.Ala348Thr	missense	Exon 9 of 9	NP_620775.2	Q6UWZ7-1
	ABRAXAS1	NM_001345962.2		c.715G>A	p.Ala239Thr	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.1042G>A	p.Ala348Thr	missense	Exon 9 of 9	ENSP00000369857.3	Q6UWZ7-1
	ABRAXAS1	ENST00000856950.1		c.1030G>A	p.Ala344Thr	missense	Exon 9 of 9	ENSP00000527009.1
	ABRAXAS1	ENST00000856949.1		c.922G>A	p.Ala308Thr	missense	Exon 8 of 8	ENSP00000527008.1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54556 AN: 151930 Hom.: 11381 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.442 AC: 111166 AN: 251352 AF XY: 0.439

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.668

Gnomad FIN exome AF: 0.463

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.417 AC: 609371 AN: 1461480 Hom.: 131399 Cov.: 46 AF XY: 0.418 AC XY: 303896 AN XY: 727052

African (AFR) AF: 0.149 AC: 4988 AN: 33474

American (AMR) AF: 0.587 AC: 26245 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7524 AN: 26126

East Asian (EAS) AF: 0.642 AC: 25459 AN: 39672

South Asian (SAS) AF: 0.465 AC: 40116 AN: 86244

European-Finnish (FIN) AF: 0.465 AC: 24837 AN: 53420

Middle Eastern (MID) AF: 0.298 AC: 1686 AN: 5656

European-Non Finnish (NFE) AF: 0.408 AC: 453832 AN: 1111790

Other (OTH) AF: 0.409 AC: 24684 AN: 60374

GnomAD4 genome AF: 0.359 AC: 54603 AN: 152048 Hom.: 11400 Cov.: 32 AF XY: 0.368 AC XY: 27361 AN XY: 74326

African (AFR) AF: 0.166 AC: 6905 AN: 41514

American (AMR) AF: 0.472 AC: 7202 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 1001 AN: 3470

East Asian (EAS) AF: 0.667 AC: 3446 AN: 5164

South Asian (SAS) AF: 0.491 AC: 2364 AN: 4818

European-Finnish (FIN) AF: 0.455 AC: 4808 AN: 10556

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27734 AN: 67940

Other (OTH) AF: 0.342 AC: 722 AN: 2110

Alfa AF: 0.381 Hom.: 35663

Bravo AF: 0.350

TwinsUK AF: 0.414 AC: 1535

ALSPAC AF: 0.402 AC: 1548

ESP6500AA AF: 0.170 AC: 747

ESP6500EA AF: 0.408 AC: 3509

ExAC AF: 0.431 AC: 52305

Asia WGS AF: 0.581 AC: 2016 AN: 3478

EpiCase AF: 0.385

EpiControl AF: 0.377

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0000038	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.56
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.15
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		0.82	P
Vest4		0.015
MPC		0.12
ClinPred		0.0095	T
GERP RS		2.8
Varity_R		0.035
gMVP		0.26
Mutation Taster		=98/2	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: rs12642536; hg19: chr4-84383810; COSMIC: COSV55030147; COSMIC: COSV55030147;