chr2-9494727-A-G

Variant names:

• chr2-9494727-A-G
• rs1048610
• NM_003183.6:c.1824T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003183.6(ADAM17):​c.1824T>C​(p.Ser608Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,613,660 control chromosomes in the GnomAD database, including 270,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27271 hom., cov: 31)
  • Exomes 𝑓: 0.57 (243008 hom.)
• Consequence: ADAM17 NM_003183.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.513
• Publications: 36 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-9494727-A-G is Benign according to our data. Variant chr2-9494727-A-G is described in ClinVar as Benign. ClinVar VariationId is 1169868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.513 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003183.6. 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
	ADAM17	NM_003183.6	MANE Select	c.1824T>C	p.Ser608Ser	synonymous	Exon 15 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.1164T>C	p.Ser388Ser	synonymous	Exon 15 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.927T>C	p.Ser309Ser	synonymous	Exon 15 of 19	NP_001369707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.1824T>C	p.Ser608Ser	synonymous	Exon 15 of 19	ENSP00000309968.3	P78536-1
	ADAM17	ENST00000926352.1		c.1902T>C	p.Ser634Ser	synonymous	Exon 16 of 20	ENSP00000596411.1
	ADAM17	ENST00000945284.1		c.1854T>C	p.Ser618Ser	synonymous	Exon 15 of 19	ENSP00000615343.1

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88640 AN: 151888 Hom.: 27239 Cov.: 31

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.0926

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.611

GnomAD2 exomes AF: 0.500 AC: 125705 AN: 251400 AF XY: 0.508

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.628

Gnomad EAS exome AF: 0.0920

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.565 AC: 826280 AN: 1461654 Hom.: 243008 Cov.: 49 AF XY: 0.564 AC XY: 410270 AN XY: 727116

African (AFR) AF: 0.725 AC: 24259 AN: 33472

American (AMR) AF: 0.316 AC: 14150 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 16515 AN: 26130

East Asian (EAS) AF: 0.0642 AC: 2548 AN: 39692

South Asian (SAS) AF: 0.460 AC: 39703 AN: 86232

European-Finnish (FIN) AF: 0.488 AC: 26070 AN: 53416

Middle Eastern (MID) AF: 0.670 AC: 3862 AN: 5766

European-Non Finnish (NFE) AF: 0.598 AC: 664671 AN: 1111840

Other (OTH) AF: 0.571 AC: 34502 AN: 60384

GnomAD4 genome AF: 0.584 AC: 88716 AN: 152006 Hom.: 27271 Cov.: 31 AF XY: 0.569 AC XY: 42280 AN XY: 74294

African (AFR) AF: 0.712 AC: 29531 AN: 41470

American (AMR) AF: 0.446 AC: 6816 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3470

East Asian (EAS) AF: 0.0923 AC: 478 AN: 5180

South Asian (SAS) AF: 0.439 AC: 2115 AN: 4816

European-Finnish (FIN) AF: 0.466 AC: 4899 AN: 10524

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40551 AN: 67956

Other (OTH) AF: 0.607 AC: 1280 AN: 2108

Alfa AF: 0.591 Hom.: 76055

Bravo AF: 0.585

Asia WGS AF: 0.315 AC: 1097 AN: 3478

EpiCase AF: 0.601

EpiControl AF: 0.602

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Inflammatory skin and bowel disease, neonatal, 1 (2)
-	-	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.9
DANN	Benign	0.70
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs1048610; hg19: chr2-9634856; COSMIC: COSV108127573; COSMIC: COSV108127573;