Variant chr4-176225269-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_080874.4(ASB5):c.269T>C(p.Leu90Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,459,418 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: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ASB5
NM_080874.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.37

Variant links:

Genes affected

ASB5 (HGNC:17180): (ankyrin repeat and SOCS box containing 5) 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. Multiple alternatively spliced transcript variants have been described for this gene but their full length sequences are not known. [provided by RefSeq, Jul 2008]

ASB5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ASB5	NM_080874.4 linkuse as main transcript	c.269T>C	p.Leu90Ser	missense_variant	2/7	ENST00000296525.7
ASB5	NM_001410863.1 linkuse as main transcript	c.134T>C	p.Leu45Ser	missense_variant	2/7
ASB5	XM_005262759.2 linkuse as main transcript	c.269T>C	p.Leu90Ser	missense_variant	4/9
ASB5	XM_011531617.4 linkuse as main transcript	c.110T>C	p.Leu37Ser	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASB5	ENST00000296525.7 linkuse as main transcript	c.269T>C	p.Leu90Ser	missense_variant	2/7	1	NM_080874.4	P1	Q8WWX0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251404

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135876

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1459418

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726258

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:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The c.269T>C (p.L90S) alteration is located in exon 2 (coding exon 2) of the ASB5 gene. This alteration results from a T to C substitution at nucleotide position 269, causing the leucine (L) at amino acid position 90 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

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

D;.

Vest4

0.84

MutPred

0.83

Loss of stability (P = 0.0961);.;

MVP

0.90

MPC

0.40

ClinPred

0.99

GERP RS

6.2

Varity_R

0.58

gMVP

0.86

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

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