15-100629743-A-G

Variant names:

• chr15-100629743-A-G
• rs770765024
• NM_198243.3:c.518A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198243.3(ASB7):​c.518A>G​(p.Asn173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ASB7 NM_198243.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

Genes affected

ASB7 (HGNC:17182): (ankyrin repeat and SOCS box containing 7) The protein encoded by this gene belongs to a family of ankyrin repeat proteins that, along with four other protein families, contains a C-terminal SOCS box motif. Growing evidence suggests that the SOCS 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. In this way, SOCS box containing proteins may regulate protein turnover by targeting proteins for polyubiquination and, therefore, for proteasome-mediated degradation. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05887103).
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB7	NM_198243.3	c.518A>G	p.Asn173Ser	missense_variant	Exon 5 of 6	ENST00000332783.12	NP_937886.1
ASB7	NM_024708.4	c.518A>G	p.Asn173Ser	missense_variant	Exon 5 of 5		NP_078984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB7	ENST00000332783.12	c.518A>G	p.Asn173Ser	missense_variant	Exon 5 of 6	1	NM_198243.3	ENSP00000328327.8
ASB7	ENST00000343276.4	c.518A>G	p.Asn173Ser	missense_variant	Exon 5 of 5	1		ENSP00000339819.4
ASB7	ENST00000558747.5	c.211+17316A>G		intron_variant	Intron 4 of 4	5		ENSP00000453626.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.000955

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251456 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000537

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: 0.0000243

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00137

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: 0.000955

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.518A>G (p.N173S) alteration is located in exon 5 (coding exon 2) of the ASB7 gene. This alteration results from a A to G substitution at nucleotide position 518, causing the asparagine (N) at amino acid position 173 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	0.057
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.19
Sift	Benign	0.36	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;B
Vest4		0.13
MutPred		0.51		Loss of catalytic residue at N173 (P = 9e-04);Loss of catalytic residue at N173 (P = 9e-04);
MVP		0.42
MPC		0.91
ClinPred		0.055	T
GERP RS		1.7
Varity_R		0.034
gMVP		0.14

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: rs770765024; hg19: chr15-101169948;