Genetic Variant ASB6:p.Cys313Ser (chr9-129638118-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017873.4(ASB6):c.938G>C(p.Cys313Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ASB6
NM_017873.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Variant links:

Genes affected

ASB6 (HGNC:17181): (ankyrin repeat and SOCS box containing 6) The protein encoded by this gene belongs to a family of ankyrin repeat proteins that, along with four other protein families, contain a C-terminal SOCS box motif. Growing evidence suggests that the SOCS box, similar to the F-box, acts as a bridge between specific substrate-binding domains and the more generic proteins that comprise a large family of E3 ubiquitin protein ligases. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]

ASB6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07648748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB6	NM_017873.4 link	c.938G>C	p.Cys313Ser	missense_variant	Exon 6 of 6	ENST00000277458.5	NP_060343.1	Q9NWX5-1
ASB6	NM_001202403.2 link	c.851G>C	p.Cys284Ser	missense_variant	Exon 5 of 5		NP_001189332.1	Q9NWX5F6TX30
ASB6	NM_177999.3 link	c.*235G>C		3_prime_UTR_variant	Exon 5 of 5		NP_821066.1	Q9NWX5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ASB6	ENST00000277458.5 link	c.938G>C	p.Cys313Ser	missense_variant	Exon 6 of 6	1	NM_017873.4	ENSP00000277458.4	Q9NWX5-1
ASB6	ENST00000450050.6 link	c.851G>C	p.Cys284Ser	missense_variant	Exon 5 of 5	1		ENSP00000416172.3	F6TX30
ASB6	ENST00000277459 link	c.*235G>C		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000277459.4	Q9NWX5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251232

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.938G>C (p.C313S) alteration is located in exon 6 (coding exon 6) of the ASB6 gene. This alteration results from a G to C substitution at nucleotide position 938, causing the cysteine (C) at amino acid position 313 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.076

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.21

.;N

REVEL

Benign

0.19

Sift

Benign

0.78

.;T

Sift4G

Benign

0.76

T;T

Polyphen

0.033

.;B

Vest4

0.15

MutPred

0.37

.;Gain of disorder (P = 0.0061);

MVP

0.50

MPC

0.42

ClinPred

0.036

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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