9-129637870-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017873.4(ASB6):​c.1186G>T​(p.Val396Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V396L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ASB6 NM_017873.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25523087).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017873.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASB6	NM_017873.4	MANE Select	c.1186G>T	p.Val396Phe	missense	Exon 6 of 6	NP_060343.1	Q9NWX5-1
	ASB6	NM_001202403.2		c.1099G>T	p.Val367Phe	missense	Exon 5 of 5	NP_001189332.1	F6TX30
	ASB6	NM_177999.3		c.*483G>T		3_prime_UTR	Exon 5 of 5	NP_821066.1	Q9NWX5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASB6	ENST00000277458.5	TSL:1 MANE Select	c.1186G>T	p.Val396Phe	missense	Exon 6 of 6	ENSP00000277458.4	Q9NWX5-1
	ASB6	ENST00000450050.6	TSL:1	c.1099G>T	p.Val367Phe	missense	Exon 5 of 5	ENSP00000416172.3	F6TX30
	ASB6	ENST00000277459.8	TSL:1	c.*483G>T		3_prime_UTR	Exon 5 of 5	ENSP00000277459.4	Q9NWX5-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396740 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 687810

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31390

American (AMR) AF: 0.00 AC: 0 AN: 35208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21732

East Asian (EAS) AF: 0.00 AC: 0 AN: 39162

South Asian (SAS) AF: 0.00 AC: 0 AN: 75046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080290

Other (OTH) AF: 0.00 AC: 0 AN: 57502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.047
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0030	B
Vest4		0.46
MutPred		0.67		Gain of methylation at K395 (P = 0.2009)
MVP		0.48
MPC		1.1
ClinPred		0.84	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.85
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs374558502; hg19: chr9-132400149;