rs376489465

Variant names:

• chr4-83462758-T-C
• rs376489465
• NM_139076.3:c.941A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-83462758-T-C
• chr4-83462758-T-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_139076.3(ABRAXAS1):​c.941A>G​(p.Asn314Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. N314N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0300
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049249172).
• BP6: Variant 4-83462758-T-C is Benign according to our data. Variant chr4-83462758-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496543.

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.941A>G	p.Asn314Ser	missense	Exon 9 of 9	NP_620775.2	Q6UWZ7-1
	ABRAXAS1	NM_001345962.2		c.614A>G	p.Asn205Ser	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.941A>G	p.Asn314Ser	missense	Exon 9 of 9	ENSP00000369857.3	Q6UWZ7-1
	ABRAXAS1	ENST00000856950.1		c.929A>G	p.Asn310Ser	missense	Exon 9 of 9	ENSP00000527009.1
	ABRAXAS1	ENST00000856949.1		c.821A>G	p.Asn274Ser	missense	Exon 8 of 8	ENSP00000527008.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251298 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461658 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727136

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111950

Other (OTH) AF: 0.000248 AC: 15 AN: 60370

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74516

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.00809 AC: 28 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.36
DANN	Benign	0.43
DEOGEN2	Benign	0.00046	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.030
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.038
Sift	Benign	0.35	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.015
MVP		0.20
MPC		0.080
ClinPred		0.025	T
GERP RS		-9.2
Varity_R		0.014
gMVP		0.092
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: rs376489465; hg19: chr4-84383911;