4-176221579-C-T

Variant names:

• chr4-176221579-C-T
• NM_080874.4:c.406G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080874.4(ASB5):​c.406G>A​(p.Gly136Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASB5 NM_080874.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30

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]

ACMG classification

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, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB5	NM_080874.4	c.406G>A	p.Gly136Ser	missense_variant	Exon 4 of 7	ENST00000296525.7	NP_543150.1
ASB5	NM_001410863.1	c.271G>A	p.Gly91Ser	missense_variant	Exon 4 of 7		NP_001397792.1
ASB5	XM_005262759.2	c.406G>A	p.Gly136Ser	missense_variant	Exon 6 of 9		XP_005262816.1
ASB5	XM_011531617.4	c.247G>A	p.Gly83Ser	missense_variant	Exon 4 of 7		XP_011529919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB5	ENST00000296525.7	c.406G>A	p.Gly136Ser	missense_variant	Exon 4 of 7	1	NM_080874.4	ENSP00000296525.3
ASB5	ENST00000672074.1	c.271G>A	p.Gly91Ser	missense_variant	Exon 4 of 7			ENSP00000500617.1
ASB5	ENST00000512254.1	c.247G>A	p.Gly83Ser	missense_variant	Exon 4 of 7	2		ENSP00000422877.1
ASB5	ENST00000511879.1	n.491G>A		non_coding_transcript_exon_variant	Exon 4 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406G>A (p.G136S) alteration is located in exon 4 (coding exon 4) of the ASB5 gene. This alteration results from a G to A substitution at nucleotide position 406, causing the glycine (G) at amino acid position 136 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	Benign	0.27
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.022	D;T
Polyphen		0.99	D;.
Vest4		0.86
MutPred		0.84		Loss of catalytic residue at I134 (P = 0.2748);.;
MVP		0.89
MPC		0.37
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.50
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr4-177142730;