4-176215694-A-G

Variant names:

• chr4-176215694-A-G
• NM_080874.4:c.896T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_080874.4(ASB5):​c.896T>C​(p.Leu299Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASB5 NM_080874.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB5	NM_080874.4	c.896T>C	p.Leu299Pro	missense_variant	Exon 7 of 7	ENST00000296525.7	NP_543150.1
ASB5	NM_001410863.1	c.761T>C	p.Leu254Pro	missense_variant	Exon 7 of 7		NP_001397792.1
ASB5	XM_005262759.2	c.896T>C	p.Leu299Pro	missense_variant	Exon 9 of 9		XP_005262816.1
ASB5	XM_011531617.4	c.737T>C	p.Leu246Pro	missense_variant	Exon 7 of 7		XP_011529919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB5	ENST00000296525.7	c.896T>C	p.Leu299Pro	missense_variant	Exon 7 of 7	1	NM_080874.4	ENSP00000296525.3
ASB5	ENST00000672074.1	c.761T>C	p.Leu254Pro	missense_variant	Exon 7 of 7			ENSP00000500617.1
ASB5	ENST00000512254.1	c.737T>C	p.Leu246Pro	missense_variant	Exon 7 of 7	2		ENSP00000422877.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460838 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726760

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.896T>C (p.L299P) alteration is located in exon 7 (coding exon 7) of the ASB5 gene. This alteration results from a T to C substitution at nucleotide position 896, causing the leucine (L) at amino acid position 299 to be replaced by a proline (P). 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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.69		Gain of helix (P = 0.0034);.;
MVP		0.76
MPC		0.45
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-177136845;