7-87934479-T-G

Position:

• chr7-87934479-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001324418.2(ADAM22):​c.14T>G​(p.Val5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,602,980 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (34 hom.)
• Consequence: ADAM22 NM_001324418.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.115

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035004914).
• BP6: Variant 7-87934479-T-G is Benign according to our data. Variant chr7-87934479-T-G is described in ClinVar as [Benign]. Clinvar id is 773214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00108 (1563/1450812) while in subpopulation AMR AF= 0.0282 (1243/44078). AF 95% confidence interval is 0.0269. There are 34 homozygotes in gnomad4_exome. There are 637 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM22	NM_001324418.2	c.14T>G	p.Val5Gly	missense_variant	1/32	ENST00000413139.2	NP_001311347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM22	ENST00000413139.2	c.14T>G	p.Val5Gly	missense_variant	1/32	5	NM_001324418.2	ENSP00000412085.2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152056 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00701

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00568 AC: 1290 AN: 227074 Hom.: 29 AF XY: 0.00417 AC XY: 520 AN XY: 124782

Gnomad AFR exome AF: 0.000731

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.00145

Gnomad EAS exome AF: 0.00732

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00108 AC: 1563 AN: 1450812 Hom.: 34 Cov.: 31 AF XY: 0.000883 AC XY: 637 AN XY: 721528

Gnomad4 AFR exome AF: 0.000331

Gnomad4 AMR exome AF: 0.0282

Gnomad4 ASJ exome AF: 0.00143

Gnomad4 EAS exome AF: 0.00330

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.0000793

Gnomad4 OTH exome AF: 0.000850

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152168 Hom.: 5 Cov.: 31 AF XY: 0.00128 AC XY: 95 AN XY: 74372

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00703

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000588 Hom.: 0

Bravo AF: 0.00286

ESP6500AA AF: 0.000956 AC: 4

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00439 AC: 529

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ADAM22-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 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	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.019	.;T;T;.;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.74	T;T;T;T;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;.;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.47	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.021	D;T;D;D;D;D
Sift4G	Uncertain	0.038	D;T;T;D;D;D
Polyphen		0.0020	B;B;.;.;B;B
Vest4		0.29
MVP		0.45
MPC		0.66
ClinPred		0.0065	T
GERP RS		2.4
Varity_R		0.077
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs201972241; hg19: chr7-87563794;