chr2-9492963-C-T

Variant names:

• chr2-9492963-C-T
• rs61754177
• NM_003183.6:c.2017G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000310823.8(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 (★★). Synonymous variant affecting the same amino acid position (i.e. V673V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (58 hom.)
• Consequence: ADAM17 ENST00000310823.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.57
• Publications: 14 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 539952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000310823.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.2017G>A	p.Val673Ile	missense	Exon 17 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.1357G>A	p.Val453Ile	missense	Exon 17 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.1120G>A	p.Val374Ile	missense	Exon 17 of 19	NP_001369707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.2017G>A	p.Val673Ile	missense	Exon 17 of 19	ENSP00000309968.3
	ADAM17	ENST00000699318.1		c.1927G>A	p.Val643Ile	missense	Exon 16 of 18	ENSP00000514297.1
	ADAM17	ENST00000647610.1		n.*1477G>A		non_coding_transcript_exon	Exon 13 of 15	ENSP00000497929.1

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

GnomAD2 exomes AF: 0.00870 AC: 2158 AN: 247906 AF XY: 0.00770

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 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

African (AFR) AF: 0.00153 AC: 51 AN: 33368

American (AMR) AF: 0.0247 AC: 1099 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00256 AC: 220 AN: 85864

European-Finnish (FIN) AF: 0.00529 AC: 282 AN: 53340

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00801 AC: 8898 AN: 1110570

Other (OTH) AF: 0.00690 AC: 416 AN: 60248

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

African (AFR) AF: 0.00289 AC: 120 AN: 41560

American (AMR) AF: 0.0128 AC: 196 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00881 AC: 599 AN: 68024

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00765 Hom.: 11

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Inflammatory skin and bowel disease, neonatal, 1 (2)
-	-	1	ADAM17-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.6
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
Vest4		0.57
MVP		0.59
MPC		1.1
ClinPred		0.041	T
GERP RS		5.7
Varity_R		0.45
gMVP		0.79
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs61754177; hg19: chr2-9633092; COSMIC: COSV107397858; COSMIC: COSV107397858;