9-129637870-C-G

Variant names:

• chr9-129637870-C-G
• rs374558502
• NM_017873.4:c.1186G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017873.4(ASB6):​c.1186G>C​(p.Val396Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000433 in 1,549,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: ASB6 NM_017873.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

Genes affected

ASB6 (HGNC:17181): (ankyrin repeat and SOCS box containing 6) The protein encoded by this gene belongs to a family of ankyrin repeat proteins that, along with four other protein families, contain a C-terminal SOCS box motif. Growing evidence suggests that the SOCS box, similar to the F-box, acts as a bridge between specific substrate-binding domains and the more generic proteins that comprise a large family of E3 ubiquitin protein ligases. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029860377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB6	NM_017873.4	c.1186G>C	p.Val396Leu	missense_variant	Exon 6 of 6	ENST00000277458.5	NP_060343.1
ASB6	NM_001202403.2	c.1099G>C	p.Val367Leu	missense_variant	Exon 5 of 5		NP_001189332.1
ASB6	NM_177999.3	c.*483G>C		3_prime_UTR_variant	Exon 5 of 5		NP_821066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB6	ENST00000277458.5	c.1186G>C	p.Val396Leu	missense_variant	Exon 6 of 6	1	NM_017873.4	ENSP00000277458.4
ASB6	ENST00000450050.6	c.1099G>C	p.Val367Leu	missense_variant	Exon 5 of 5	1		ENSP00000416172.3
ASB6	ENST00000277459	c.*483G>C		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000277459.4

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000952 AC: 19 AN: 199662 Hom.: 0 AF XY: 0.0000849 AC XY: 9 AN XY: 105990

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000495

Gnomad ASJ exome AF: 0.000926

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000422 AC: 59 AN: 1396740 Hom.: 0 Cov.: 29 AF XY: 0.0000509 AC XY: 35 AN XY: 687810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000540

Gnomad4 ASJ exome AF: 0.000966

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000833

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000413 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1186G>C (p.V396L) alteration is located in exon 6 (coding exon 6) of the ASB6 gene. This alteration results from a G to C substitution at nucleotide position 1186, causing the valine (V) at amino acid position 396 to be replaced by a leucine (L). 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	0.57
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.033
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.030	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.69	.;N
REVEL	Benign	0.14
Sift	Benign	0.20	.;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.027	.;B
Vest4		0.12
MVP		0.28
MPC		0.47
ClinPred		0.088	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.090
gMVP		0.60

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

Other links and lift over

dbSNP: rs374558502; hg19: chr9-132400149;