Genetic Variant ASB12:p.Met309Ile (chrX-64224365-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_130388.4(ASB12):c.927G>A(p.Met309Ile) 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 1,209,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., 18 hem., cov: 23)

Exomes 𝑓: 0.000052 ( 0 hom. 12 hem. )

Consequence

ASB12
NM_130388.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0150

Variant links:

Genes affected

ASB12 (HGNC:19763): (ankyrin repeat and SOCS box containing 12) 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 a 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. [provided by RefSeq, Jan 2011]

ASB12 links:

LOC112268307 (HGNC:):

LOC112268307 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017632037).

BS2

High Hemizygotes in GnomAd4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB12	NM_130388.4 link	c.927G>A	p.Met309Ile	missense_variant	Exon 3 of 3	ENST00000362002.3	NP_569059.3	Q8WXK4-2
LOC112268307	XM_047442705.1 link	c.125+17325C>T		intron_variant	Intron 2 of 4		XP_047298661.1
LOC112268307	XM_047442706.1 link	c.125+17325C>T		intron_variant	Intron 2 of 3		XP_047298662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB12	ENST00000362002.3 link	c.927G>A	p.Met309Ile	missense_variant	Exon 3 of 3	2	NM_130388.4	ENSP00000355195.2		Q8WXK4-2
ENSG00000287370	ENST00000671386.1 link	n.171-9026C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

AN:

111382

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

AN XY:

33570

show subpopulations

Gnomad AFR

AF:

0.00235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000953

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:

0.00

Gnomad OTH

AF:

0.000665

GnomAD3 exomes

AF:

0.000114

AC:

AN:

183412

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

67852

show subpopulations

Gnomad AFR exome

AF:

0.00152

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:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1097715

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

363079

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000664

AC:

AN:

111436

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

AN XY:

33634

show subpopulations

Gnomad4 AFR

AF:

0.00235

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000656

Alfa

AF:

0.0000706

Hom.:

Bravo

AF:

0.000842

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.927G>A (p.M309I) alteration is located in exon 3 (coding exon 2) of the ASB12 gene. This alteration results from a G to A substitution at nucleotide position 927, causing the methionine (M) at amino acid position 309 to be replaced by an isoleucine (I). 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

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.86

CADD

Benign

7.6

DANN

Benign

0.90

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.72

M_CAP

Benign

0.0024

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.34

REVEL

Benign

0.070

Sift

Benign

0.45

Sift4G

Benign

0.24

Vest4

0.14

MVP

0.64

MPC

0.0088

ClinPred

0.011

GERP RS

1.1

gMVP

0.20

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