Genetic Variant ASB15:p.Leu237Phe (chr7-123627121-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001290258.2(ASB15):c.709C>T(p.Leu237Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,612,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

ASB15
NM_001290258.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.166

Variant links:

Genes affected

ASB15 (HGNC:19767): (ankyrin repeat and SOCS box containing 15) This gene encodes a member of the suppressor of cytokine signaling box superfamily. The proteins in this superfamily participate in the ubiquitin-proteasome system for the degradation of proteins in the cell cycle and signal transduction pathways. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ASB15 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035586953).

BP6

Variant 7-123627121-C-T is Benign according to our data. Variant chr7-123627121-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2465885.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB15	NM_001290258.2 link	c.709C>T	p.Leu237Phe	missense_variant	Exon 9 of 12	ENST00000451215.6	NP_001277187.1	Q8WXK1A0A384NYV2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB15	ENST00000451215.6 link	c.709C>T	p.Leu237Phe	missense_variant	Exon 9 of 12	2	NM_001290258.2	ENSP00000416433.1		Q8WXK1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250482

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135332

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:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1460790

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726592

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:

0.0000747

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 08, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.015

T;T;T;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.28

.;.;.;T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.036

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;L;.;.;L

PrimateAI

Benign

0.27

PROVEAN

Benign

0.12

N;N;N;.;N;N

REVEL

Benign

0.024

Sift

Benign

0.73

T;T;T;.;T;T

Sift4G

Benign

0.54

T;T;T;T;T;T

Polyphen

0.0

B;B;B;.;.;B

Vest4

0.18

MutPred

0.44

Gain of catalytic residue at L237 (P = 0.0352);Gain of catalytic residue at L237 (P = 0.0352);Gain of catalytic residue at L237 (P = 0.0352);.;Gain of catalytic residue at L237 (P = 0.0352);Gain of catalytic residue at L237 (P = 0.0352);

MVP

0.16

MPC

0.15

ClinPred

0.014

GERP RS

0.66

Varity_R

0.039

gMVP

0.14

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