dbSNP rs7829965: ADAM28:p.Met684Ile (chr8-24349925-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014265.6(ADAM28):c.2052G>A(p.Met684Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,246 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.054 ( 316 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1664 hom. )

Consequence

ADAM28
NM_014265.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0210

Publications

18 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014255345).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM28	NM_014265.6 link	c.2052G>A	p.Met684Ile	missense_variant	Exon 19 of 23	ENST00000265769.9	NP_055080.2	Q9UKQ2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM28	ENST00000265769.9 link	c.2052G>A	p.Met684Ile	missense_variant	Exon 19 of 23	1	NM_014265.6	ENSP00000265769.4		Q9UKQ2-1

Frequencies

GnomAD3 genomes

AF:

0.0534

AC:

8121

AN:

151972

Hom.:

312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0332

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.0974

Gnomad FIN

AF:

0.0321

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0284

Gnomad OTH

AF:

0.0436

GnomAD2 exomes

AF:

0.0466

AC:

11704

AN:

251202

AF XY:

0.0470

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0333

Gnomad ASJ exome

AF:

0.0162

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0319

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0318

GnomAD4 exome

AF:

0.0375

AC:

54748

AN:

1461156

Hom.:

1664

Cov.:

AF XY:

0.0388

AC XY:

28226

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.106

AC:

3556

AN:

33436

American (AMR)

AF:

0.0333

AC:

1487

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0175

AC:

457

AN:

26112

East Asian (EAS)

AF:

0.124

AC:

4909

AN:

39622

South Asian (SAS)

AF:

0.0944

AC:

8135

AN:

86160

European-Finnish (FIN)

AF:

0.0314

AC:

1677

AN:

53396

Middle Eastern (MID)

AF:

0.0274

AC:

158

AN:

5764

European-Non Finnish (NFE)

AF:

0.0288

AC:

32031

AN:

1111604

Other (OTH)

AF:

0.0387

AC:

2338

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

2821

5642

8462

11283

14104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1434

2868

4302

5736

7170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0536

AC:

8151

AN:

152090

Hom.:

316

Cov.:

AF XY:

0.0538

AC XY:

4001

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.101

AC:

4204

AN:

41490

American (AMR)

AF:

0.0332

AC:

507

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3468

East Asian (EAS)

AF:

0.103

AC:

532

AN:

5152

South Asian (SAS)

AF:

0.0963

AC:

463

AN:

4810

European-Finnish (FIN)

AF:

0.0321

AC:

340

AN:

10584

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0284

AC:

1933

AN:

68000

Other (OTH)

AF:

0.0446

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

378

756

1135

1513

1891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0366

Hom.:

718

Bravo

AF:

0.0548

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.101

AC:

443

ESP6500EA

AF:

0.0276

AC:

237

ExAC

AF:

0.0490

AC:

5945

Asia WGS

AF:

0.117

AC:

404

AN:

3478

EpiCase

AF:

0.0237

EpiControl

AF:

0.0237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.3

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.0058

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0014

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

PhyloP100

0.021

PrimateAI

Benign

0.31

PROVEAN

Benign

0.84

REVEL

Benign

0.035

Sift

Benign

1.0

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.053

MutPred

0.42

Loss of sheet (P = 7e-04);

MPC

0.040

ClinPred

0.0023

GERP RS

-0.58

Varity_R

0.032

gMVP

0.20

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over