Variant 8-24320275-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014265.6(ADAM28):c.616A>G(p.Ile206Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,603,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

ADAM28
NM_014265.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0830

Variant links:

Genes affected

ADAM28 (HGNC:206): (ADAM metallopeptidase domain 28) 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. The protein encoded by this gene is a lymphocyte-expressed ADAM protein. This gene is present in a gene cluster with other members of the ADAM family on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ADAM28 links:

ADAM7-AS1 (HGNC:56152): (ADAM7, ADAMDEC1 and ADAM28 antisense RNA 1)

ADAM7-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.032110333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM28	NM_014265.6 linkuse as main transcript	c.616A>G	p.Ile206Val	missense_variant	7/23	ENST00000265769.9	NP_055080.2
ADAM7-AS1	NR_125808.1 linkuse as main transcript	n.502-19346T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM28	ENST00000265769.9 linkuse as main transcript	c.616A>G	p.Ile206Val	missense_variant	7/23	1	NM_014265.6	ENSP00000265769	A2	Q9UKQ2-1
ADAM7-AS1	ENST00000519689.1 linkuse as main transcript	n.607-19346T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000282

AC:

AN:

248116

Hom.:

AF XY:

0.000231

AC XY:

AN XY:

134200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000267

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000293

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000173

AC:

251

AN:

1451786

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

146

AN XY:

722674

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.000248

Gnomad4 ASJ exome

AF:

0.00200

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.000167

GnomAD4 genome

AF:

0.000204

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000264

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000297

AC:

EpiCase

AF:

0.000494

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.616A>G (p.I206V) alteration is located in exon 7 (coding exon 7) of the ADAM28 gene. This alteration results from a A to G substitution at nucleotide position 616, causing the isoleucine (I) at amino acid position 206 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.56

CADD

Benign

3.5

DANN

Benign

0.91

DEOGEN2

Benign

0.0089

T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.040

N;N

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.065

Sift

Benign

0.32

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.020

B;B

Vest4

0.15

MVP

0.45

MPC

0.038

ClinPred

0.69

GERP RS

1.7

Varity_R

0.060

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over