X-64224995-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_130388.4(ASB12):​c.656G>A​(p.Arg219His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,203,311 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 3 hem., cov: 22)
Exomes 𝑓: 0.000044 ( 0 hom. 15 hem. )

Consequence

ASB12
NM_130388.4 missense

Scores

1
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.122038096).
BS2
High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASB12NM_130388.4 linkc.656G>A p.Arg219His missense_variant Exon 2 of 3 ENST00000362002.3 NP_569059.3 Q8WXK4-2
LOC112268307XM_047442705.1 linkc.125+17955C>T intron_variant Intron 2 of 4 XP_047298661.1
LOC112268307XM_047442706.1 linkc.125+17955C>T intron_variant Intron 2 of 3 XP_047298662.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASB12ENST00000362002.3 linkc.656G>A p.Arg219His missense_variant Exon 2 of 3 2 NM_130388.4 ENSP00000355195.2 Q8WXK4-2
ENSG00000287370ENST00000671386.1 linkn.171-8396C>T intron_variant Intron 2 of 2

Frequencies

GnomAD3 genomes
AF:
0.0000804
AC:
9
AN:
111975
Hom.:
0
Cov.:
22
AF XY:
0.0000879
AC XY:
3
AN XY:
34149
show subpopulations
Gnomad AFR
AF:
0.0000325
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000188
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:
0.000113
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000527
AC:
9
AN:
170890
Hom.:
0
AF XY:
0.0000327
AC XY:
2
AN XY:
61138
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000192
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000552
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000393
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000440
AC:
48
AN:
1091336
Hom.:
0
Cov.:
32
AF XY:
0.0000417
AC XY:
15
AN XY:
359438
show subpopulations
Gnomad4 AFR exome
AF:
0.000153
Gnomad4 AMR exome
AF:
0.000206
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000339
Gnomad4 SAS exome
AF:
0.000150
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000322
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000804
AC:
9
AN:
111975
Hom.:
0
Cov.:
22
AF XY:
0.0000879
AC XY:
3
AN XY:
34149
show subpopulations
Gnomad4 AFR
AF:
0.0000325
Gnomad4 AMR
AF:
0.000188
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000113
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000117
ExAC
AF:
0.0000577
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 14, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.656G>A (p.R219H) alteration is located in exon 2 (coding exon 1) of the ASB12 gene. This alteration results from a G to A substitution at nucleotide position 656, causing the arginine (R) at amino acid position 219 to be replaced by a histidine (H). 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
-0.14
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
11
DANN
Uncertain
0.98
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.84
T
PROVEAN
Benign
-0.15
N
REVEL
Benign
0.063
Sift
Benign
0.074
T
Sift4G
Benign
0.19
T
Vest4
0.085
MVP
0.86
MPC
0.0093
ClinPred
0.062
T
GERP RS
2.0
gMVP
0.65

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.

Other links and lift over

dbSNP: rs750493338; hg19: chrX-63444875; COSMIC: COSV100744683; API