rs150207999

Variant names:

• chr4-83470257-G-A
• rs150207999
• NM_139076.3:c.422C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_139076.3(ABRAXAS1):​c.422C>T​(p.Thr141Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,613,660 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (45 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.65
• Publications: 11 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009476125).
• BP6: Variant 4-83470257-G-A is Benign according to our data. Variant chr4-83470257-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 45 AR gene

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.422C>T	p.Thr141Ile	missense	Exon 5 of 9	NP_620775.2	Q6UWZ7-1
	ABRAXAS1	NM_001345962.2		c.95C>T	p.Thr32Ile	missense	Exon 4 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.422C>T	p.Thr141Ile	missense	Exon 5 of 9	ENSP00000369857.3	Q6UWZ7-1
	ABRAXAS1	ENST00000611288.4	TSL:5	c.77C>T	p.Thr26Ile	missense	Exon 1 of 5	ENSP00000482434.1	A0A087WZ78
	ABRAXAS1	ENST00000856950.1		c.422C>T	p.Thr141Ile	missense	Exon 5 of 9	ENSP00000527009.1

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 698 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00740

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00388 AC: 973 AN: 250998 AF XY: 0.00362

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00702 AC: 10259 AN: 1461428 Hom.: 45 Cov.: 30 AF XY: 0.00675 AC XY: 4906 AN XY: 727038

African (AFR) AF: 0.00105 AC: 35 AN: 33468

American (AMR) AF: 0.00264 AC: 118 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00197 AC: 170 AN: 86234

European-Finnish (FIN) AF: 0.00189 AC: 101 AN: 53416

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.00841 AC: 9354 AN: 1111694

Other (OTH) AF: 0.00741 AC: 447 AN: 60364

GnomAD4 genome AF: 0.00459 AC: 698 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.00441 AC XY: 328 AN XY: 74424

African (AFR) AF: 0.00154 AC: 64 AN: 41538

American (AMR) AF: 0.00621 AC: 95 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00740 AC: 503 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00632 Hom.: 3

Bravo AF: 0.00485

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00381 AC: 463

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00510

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.50	T
PhyloP100		7.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.67
MPC		0.53
ClinPred		0.017	T
GERP RS		5.9
PromoterAI		0.0034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.70
Mutation Taster		=94/6	polymorphism

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: rs150207999; hg19: chr4-84391410; COSMIC: COSV106097548; COSMIC: COSV106097548;