rs61754178

Variant names:

• chr2-9543235-T-C
• rs61754178
• NM_003183.6:c.148A>G

Variant summary

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

The NM_001382777.1(ADAM17):​c.-533A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00455 in 1,610,016 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (24 hom.)
• Consequence: ADAM17 NM_001382777.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.44
• 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]

ADAM17 Gene-Disease associations (from GenCC):

• inflammatory skin and bowel disease, neonatal, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067513883).
• BP6: Variant 2-9543235-T-C is Benign according to our data. Variant chr2-9543235-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 472722.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 = 0.0042 (639/152266) while in subpopulation AMR AF = 0.00752 (115/15284). AF 95% confidence interval is 0.00641. There are 1 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382777.1. 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.148A>G	p.Ile50Val	missense	Exon 2 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.-533A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.-775A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 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.148A>G	p.Ile50Val	missense	Exon 2 of 19	ENSP00000309968.3	P78536-1
	ADAM17	ENST00000478059.1	TSL:1	n.317A>G		non_coding_transcript_exon	Exon 2 of 5
	ADAM17	ENST00000618923.2	TSL:1	n.148A>G		non_coding_transcript_exon	Exon 2 of 8	ENSP00000480552.1	A6H8L4

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152148 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00595

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00376 AC: 932 AN: 248098 AF XY: 0.00384

Gnomad AFR exome AF: 0.000620

Gnomad AMR exome AF: 0.00493

Gnomad ASJ exome AF: 0.000900

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00372

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00459 AC: 6687 AN: 1457750 Hom.: 24 Cov.: 30 AF XY: 0.00449 AC XY: 3257 AN XY: 725242

African (AFR) AF: 0.000631 AC: 21 AN: 33302

American (AMR) AF: 0.00482 AC: 213 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.000947 AC: 81 AN: 85544

European-Finnish (FIN) AF: 0.00389 AC: 207 AN: 53218

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00533 AC: 5918 AN: 1109950

Other (OTH) AF: 0.00355 AC: 214 AN: 60238

GnomAD4 genome AF: 0.00420 AC: 639 AN: 152266 Hom.: 1 Cov.: 33 AF XY: 0.00423 AC XY: 315 AN XY: 74460

African (AFR) AF: 0.00103 AC: 43 AN: 41546

American (AMR) AF: 0.00752 AC: 115 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00594 AC: 404 AN: 68028

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00477 Hom.: 6

Bravo AF: 0.00412

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00368 AC: 447

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	ADAM17-related disorder (1)
-	-	1	Inflammatory skin and bowel disease, neonatal, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.11
Sift	Benign	0.30	T
Sift4G	Benign	0.12	T
Polyphen		0.62	P
Vest4		0.49
MVP		0.45
MPC		0.59
ClinPred		0.034	T
GERP RS		5.3
PromoterAI		-0.010	Neutral
Varity_R		0.14
gMVP		0.39
Mutation Taster		=96/4	polymorphism

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: rs61754178; hg19: chr2-9683364; COSMIC: COSV99072205;