chr2-9493971-G-A

Variant names:

• chr2-9493971-G-A
• rs883399
• NM_003183.6:c.1915-146C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003183.6(ADAM17):​c.1915-146C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 611,270 control chromosomes in the GnomAD database, including 89,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20448 hom., cov: 33)
  • Exomes 𝑓: 0.53 (68691 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.389
• Publications: 10 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 (BayesDel_noAF=-0.92).
• BP6: Variant 2-9493971-G-A is Benign according to our data. Variant chr2-9493971-G-A is described in ClinVar as Benign. ClinVar VariationId is 1188943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.59 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.1915-146C>T		intron	N/A	NP_003174.3
	ADAM17	NM_001382777.1		c.1255-146C>T		intron	N/A	NP_001369706.1
	ADAM17	NM_001382778.1		c.1018-146C>T		intron	N/A	NP_001369707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.1915-146C>T		intron	N/A	ENSP00000309968.3
	ADAM17	ENST00000699318.1		c.1825-146C>T		intron	N/A	ENSP00000514297.1
	IAH1	ENST00000481367.5	TSL:2	c.*64-731G>A		intron	N/A	ENSP00000419807.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76941 AN: 151910 Hom.: 20435 Cov.: 33

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.0932

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.559

GnomAD4 exome AF: 0.526 AC: 241602 AN: 459242 Hom.: 68691 AF XY: 0.526 AC XY: 127486 AN XY: 242482

African (AFR) AF: 0.457 AC: 5549 AN: 12132

American (AMR) AF: 0.353 AC: 5892 AN: 16710

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 8679 AN: 13740

East Asian (EAS) AF: 0.0619 AC: 1834 AN: 29646

South Asian (SAS) AF: 0.458 AC: 19571 AN: 42710

European-Finnish (FIN) AF: 0.487 AC: 15822 AN: 32482

Middle Eastern (MID) AF: 0.640 AC: 1359 AN: 2122

European-Non Finnish (NFE) AF: 0.595 AC: 168753 AN: 283676

Other (OTH) AF: 0.543 AC: 14143 AN: 26024

GnomAD4 genome AF: 0.506 AC: 76988 AN: 152028 Hom.: 20448 Cov.: 33 AF XY: 0.495 AC XY: 36811 AN XY: 74334

African (AFR) AF: 0.445 AC: 18448 AN: 41430

American (AMR) AF: 0.415 AC: 6339 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2181 AN: 3472

East Asian (EAS) AF: 0.0928 AC: 481 AN: 5182

South Asian (SAS) AF: 0.435 AC: 2102 AN: 4828

European-Finnish (FIN) AF: 0.468 AC: 4936 AN: 10542

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40467 AN: 67982

Other (OTH) AF: 0.556 AC: 1175 AN: 2114

Alfa AF: 0.553 Hom.: 3058

Bravo AF: 0.498

Asia WGS AF: 0.292 AC: 1016 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.77
PhyloP100		-0.39
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: rs883399; hg19: chr2-9634100; COSMIC: COSV60398674; COSMIC: COSV60398674;