4-176222419-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_080874.4(ASB5):​c.278G>A​(p.Gly93Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G93S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ASB5
NM_080874.4 missense, splice_region

Scores

10
7
2
Splicing: ADA: 0.9785
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.03
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASB5NM_080874.4 linkc.278G>A p.Gly93Asp missense_variant, splice_region_variant Exon 3 of 7 ENST00000296525.7 NP_543150.1 Q8WWX0-1Q5HYF3
ASB5NM_001410863.1 linkc.143G>A p.Gly48Asp missense_variant, splice_region_variant Exon 3 of 7 NP_001397792.1
ASB5XM_005262759.2 linkc.278G>A p.Gly93Asp missense_variant, splice_region_variant Exon 5 of 9 XP_005262816.1 Q8WWX0-1Q5HYF3
ASB5XM_011531617.4 linkc.119G>A p.Gly40Asp missense_variant, splice_region_variant Exon 3 of 7 XP_011529919.1 Q8WWX0-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASB5ENST00000296525.7 linkc.278G>A p.Gly93Asp missense_variant, splice_region_variant Exon 3 of 7 1 NM_080874.4 ENSP00000296525.3 Q8WWX0-1
ASB5ENST00000672074.1 linkc.143G>A p.Gly48Asp missense_variant, splice_region_variant Exon 3 of 7 ENSP00000500617.1 A0A5F9ZHS2
ASB5ENST00000512254.1 linkc.119G>A p.Gly40Asp missense_variant, splice_region_variant Exon 3 of 7 2 ENSP00000422877.1 Q8WWX0-2
ASB5ENST00000511879.1 linkn.363G>A splice_region_variant, non_coding_transcript_exon_variant Exon 3 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457900
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725476
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:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.56
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Uncertain
2.6
M;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.023
D;D
Sift4G
Uncertain
0.030
D;D
Polyphen
1.0
D;.
Vest4
0.88
MutPred
0.71
Loss of MoRF binding (P = 0.1057);.;
MVP
0.76
MPC
0.42
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.67
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.73
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-177143570; COSMIC: COSV56668317; COSMIC: COSV56668317; API