7-151176216-G-A

Position:

chr7-151176216-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting

The NM_001142459.2(ASB10):c.1300C>T(p.Arg434Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000641 in 1,607,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

ASB10
NM_001142459.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

ASB10 (HGNC:17185): (ankyrin repeat and SOCS box containing 10) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. The SOCS box serves to couple suppressor of cytokine signaling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2008]

ASB10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

BS2

High AC in GnomAd4 at 32 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASB10	NM_001142459.2 linkuse as main transcript	c.1300C>T	p.Arg434Cys	missense_variant	5/6	ENST00000420175.3	NP_001135931.2	Q8WXI3-1
ASB10	NM_080871.4 linkuse as main transcript	c.1255C>T	p.Arg419Cys	missense_variant	5/6		NP_543147.2	Q8WXI3-3
ASB10	NM_001142460.1 linkuse as main transcript	c.1186C>T	p.Arg396Cys	missense_variant	4/5		NP_001135932.2	Q8WXI3-2A0A090N8I2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ASB10	ENST00000420175.3 linkuse as main transcript	c.1300C>T	p.Arg434Cys	missense_variant	5/6	1	NM_001142459.2	ENSP00000391137.2	Q8WXI3-1
ASB10	ENST00000275838.5 linkuse as main transcript	c.1186C>T	p.Arg396Cys	missense_variant	4/5	1		ENSP00000275838.1	Q8WXI3-2
ASB10	ENST00000377867.7 linkuse as main transcript	c.1255C>T	p.Arg419Cys	missense_variant	5/6	2		ENSP00000367098.3	Q8WXI3-3

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000704

AC:

AN:

241522

Hom.:

AF XY:

0.0000758

AC XY:

AN XY:

131864

show subpopulations

Gnomad AFR exome

AF:

0.000453

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000834

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000488

AC:

AN:

1455290

Hom.:

Cov.:

AF XY:

0.0000511

AC XY:

AN XY:

723926

show subpopulations

Gnomad4 AFR exome

AF:

0.000391

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000210

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000555

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000146

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.1300C>T (p.R434C) alteration is located in exon 5 (coding exon 5) of the ASB10 gene. This alteration results from a C to T substitution at nucleotide position 1300, causing the arginine (R) at amino acid position 434 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 434 of the ASB10 protein (p.Arg434Cys). This variant is present in population databases (rs143907990, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ASB10-related conditions. ClinVar contains an entry for this variant (Variation ID: 2193163). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

.;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

-0.0053

MutationAssessor

Pathogenic

3.8

.;.;H

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.91

MVP

0.66

MPC

0.37

ClinPred

0.97

GERP RS

4.7

Varity_R

0.85

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over