rs17255978

Positions:

• chr7-88125600-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001324418.2(ADAM22):​c.619G>A​(p.Val207Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,590,260 control chromosomes in the GnomAD database, including 2,605 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.067 (429 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2176 hom.)
• Consequence: ADAM22 NM_001324418.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.11

Genes affected

ADAM22 (HGNC:201): (ADAM metallopeptidase domain 22) 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 biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. Unlike other members of the ADAM protein family, the protein encoded by this gene lacks metalloprotease activity since it has no zinc-binding motif. This gene is highly expressed in the brain and may function as an integrin ligand in the brain. In mice, it has been shown to be essential for correct myelination in the peripheral nervous system. Alternative splicing results in several transcript variants.[provided by RefSeq, Dec 2010]

ADAM22 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001481235).
• BP6: Variant 7-88125600-G-A is Benign according to our data. Variant chr7-88125600-G-A is described in ClinVar as [Benign]. Clinvar id is 3060180.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM22	NM_001324418.2	c.619G>A	p.Val207Ile	missense_variant	8/32	ENST00000413139.2	NP_001311347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM22	ENST00000413139.2	c.619G>A	p.Val207Ile	missense_variant	8/32	5	NM_001324418.2	ENSP00000412085.2

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10204 AN: 151942 Hom.: 421 Cov.: 32

Gnomad AFR AF: 0.0904

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.0611

Gnomad FIN AF: 0.0673

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0789

GnomAD3 exomes AF: 0.0650 AC: 15149 AN: 232904 Hom.: 704 AF XY: 0.0611 AC XY: 7738 AN XY: 126714

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0274

Gnomad SAS exome AF: 0.0600

Gnomad FIN exome AF: 0.0651

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0634

GnomAD4 exome AF: 0.0475 AC: 68315 AN: 1438202 Hom.: 2176 Cov.: 29 AF XY: 0.0475 AC XY: 33963 AN XY: 715438

Gnomad4 AFR exome AF: 0.0878

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0242

Gnomad4 SAS exome AF: 0.0610

Gnomad4 FIN exome AF: 0.0616

Gnomad4 NFE exome AF: 0.0400

Gnomad4 OTH exome AF: 0.0573

GnomAD4 genome AF: 0.0674 AC: 10243 AN: 152058 Hom.: 429 Cov.: 32 AF XY: 0.0681 AC XY: 5060 AN XY: 74342

Gnomad4 AFR AF: 0.0906

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.0611

Gnomad4 FIN AF: 0.0673

Gnomad4 NFE AF: 0.0439

Gnomad4 OTH AF: 0.0824

Alfa AF: 0.0497 Hom.: 454

Bravo AF: 0.0728

TwinsUK AF: 0.0442 AC: 164

ALSPAC AF: 0.0407 AC: 157

ESP6500AA AF: 0.0856 AC: 309

ESP6500EA AF: 0.0463 AC: 377

ExAC AF: 0.0639 AC: 7713

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ADAM22-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.010	.;T;.;T;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.84	T;T;T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N;.;N;N;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.090	N;N;N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.29	T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;.
Vest4		0.091
MPC		0.40
ClinPred		0.0099	T
GERP RS		1.4
Varity_R		0.034
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17255978; hg19: chr7-87754915;