chrX-15287961-C-T

Variant names:

• chrX-15287961-C-T
• rs781564627
• NM_080873.3:c.767G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_080873.3(ASB11):​c.767G>A​(p.Arg256His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,210,640 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 57 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R256L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 10 hem., cov: 24)
  • Exomes 𝑓: 0.00010 (0 hom. 47 hem.)
• Consequence: ASB11 NM_080873.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.560

Genes affected

ASB11 (HGNC:17186): (ankyrin repeat and SOCS box containing 11) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0777553).
• BS2: High Hemizygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB11	NM_080873.3	c.767G>A	p.Arg256His	missense_variant	Exon 6 of 7	ENST00000480796.6	NP_543149.1
ASB11	NM_001201583.2	c.716G>A	p.Arg239His	missense_variant	Exon 6 of 7		NP_001188512.1
ASB11	NM_001012428.2	c.704G>A	p.Arg235His	missense_variant	Exon 6 of 7		NP_001012428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB11	ENST00000480796.6	c.767G>A	p.Arg256His	missense_variant	Exon 6 of 7	1	NM_080873.3	ENSP00000417914.1

Frequencies

GnomAD3 genomes AF: 0.000160 AC: 18 AN: 112567 Hom.: 0 Cov.: 24 AF XY: 0.000288 AC XY: 10 AN XY: 34735

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.000363

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000153 AC: 28 AN: 183014 Hom.: 0 AF XY: 0.000178 AC XY: 12 AN XY: 67450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000769

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000724

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000734

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 113 AN: 1098073 Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 47 AN XY: 363431

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000511

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.000160 AC: 18 AN: 112567 Hom.: 0 Cov.: 24 AF XY: 0.000288 AC XY: 10 AN XY: 34735

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.000363

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.000257

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.767G>A (p.R256H) alteration is located in exon 6 (coding exon 6) of the ASB11 gene. This alteration results from a G to A substitution at nucleotide position 767, causing the arginine (R) at amino acid position 256 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	.;.;T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.32	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	.;.;L
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.096	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.40	.;.;B
Vest4		0.26
MutPred		0.38		.;.;Loss of MoRF binding (P = 0.0104);
MVP		0.94
MPC		0.057
ClinPred		0.028	T
GERP RS		1.2
Varity_R		0.19
gMVP		0.25

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: rs781564627; hg19: chrX-15306083; COSMIC: COSV60355444;