Genetic Variant ADAM28:p.His147Asn (chr8-24313443-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_014265.6(ADAM28):c.439C>A(p.His147Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,768 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 12 hom. )

Consequence

ADAM28
NM_014265.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.105

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007144958).

BP6

Variant 8-24313443-C-A is Benign according to our data. Variant chr8-24313443-C-A is described in ClinVar as [Benign]. Clinvar id is 708349.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM28	NM_014265.6 link	c.439C>A	p.His147Asn	missense_variant	Exon 6 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.439C>A	p.His147Asn	missense_variant	Exon 6 of 23	1	NM_014265.6	ENSP00000265769.4		Q9UKQ2-1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00273

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00203

AC:

509

AN:

250966

Hom.:

AF XY:

0.00207

AC XY:

281

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00302

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00144

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.00230

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00231

AC:

3375

AN:

1461498

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

1643

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00320

Gnomad4 NFE exome

AF:

0.00252

Gnomad4 OTH exome

AF:

0.00247

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152270

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00295

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.00273

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00204

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00198

AC:

240

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.028

DANN

Benign

0.53

DEOGEN2

Benign

0.0039

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.10

T;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.2

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.42

N;N

REVEL

Benign

0.0070

Sift

Benign

0.57

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0

B;B

Vest4

0.048

MVP

0.12

MPC

0.040

ClinPred

0.0025

GERP RS

-3.6

Varity_R

0.023

gMVP

0.31

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

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