chr2-9492963-C-T

Position:

• chr2-9492963-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003183.6(ADAM17):​c.2017G>A​(p.Val673Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00745 in 1,611,580 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (58 hom.)
• Consequence: ADAM17 NM_003183.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.57

Genes affected

ADAM17 (HGNC:195): (ADAM metallopeptidase domain 17) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands, and plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease patients, suggesting that the encoded protein may play a role in autoimmune disease. Additionally, this protease may play a role in viral infection through its cleavage of ACE2, the cellular receptor for SARS-CoV and SARS-CoV-2. [provided by RefSeq, Aug 2020]

IAH1 (HGNC:27696): (isoamyl acetate hydrolyzing esterase 1 (putative)) Enables identical protein binding activity. Predicted to be involved in lipid catabolic process. [provided by Alliance of Genome Resources, Apr 2022]

ADAM17 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0096232295).
• BP6: Variant 2-9492963-C-T is Benign according to our data. Variant chr2-9492963-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 539952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9492963-C-T is described in Lovd as [Likely_benign]. Variant chr2-9492963-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00657 (1001/152310) while in subpopulation AMR AF= 0.0128 (196/15306). AF 95% confidence interval is 0.0113. There are 9 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.2017G>A	p.Val673Ile	missense_variant	17/19	ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.2017G>A	p.Val673Ile	missense_variant	17/19	1	NM_003183.6	ENSP00000309968.3

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1001 AN: 152192 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00880

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00870 AC: 2158 AN: 247906 Hom.: 14 AF XY: 0.00770 AC XY: 1032 AN XY: 133990

Gnomad AFR exome AF: 0.00225

Gnomad AMR exome AF: 0.0264

Gnomad ASJ exome AF: 0.000996

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.00897

Gnomad OTH exome AF: 0.00611

GnomAD4 exome AF: 0.00754 AC: 11010 AN: 1459270 Hom.: 58 Cov.: 30 AF XY: 0.00722 AC XY: 5240 AN XY: 725836

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00256

Gnomad4 FIN exome AF: 0.00529

Gnomad4 NFE exome AF: 0.00801

Gnomad4 OTH exome AF: 0.00690

GnomAD4 genome AF: 0.00657 AC: 1001 AN: 152310 Hom.: 9 Cov.: 33 AF XY: 0.00615 AC XY: 458 AN XY: 74480

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.00881

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00730 Hom.: 5

Bravo AF: 0.00758

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00823 AC: 999

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inflammatory skin and bowel disease, neonatal, 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 12, 2022	This variant has been reported in the literature in association with inflammatory bowel disease (Gettler 2021 PMID:33359885). However, this variant is present in the Genome Aggregation Database (Highest reported MAF 1.2% (196/15286) including multiple homozygotes (https://gnomad.broadinstitute.org/variant/2-9492963-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:539952). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

ADAM17-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.90	N;.
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.57
MVP		0.59
MPC		1.1
ClinPred		0.041	T
GERP RS		5.7
Varity_R		0.45
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

LitVar

Other links and lift over

dbSNP: rs61754177; hg19: chr2-9633092;