Genetic Variant NM_021794.4:c.1076T>C (chr1-119895261-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_021794.4(ADAM30):c.1076T>C(p.Leu359Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,614,016 control chromosomes in the GnomAD database, including 14,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.17 ( 3009 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11537 hom. )

Consequence

ADAM30
NM_021794.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.24

Publications

87 publications found

Variant links:

Genes affected

ADAM30 (HGNC:208): (ADAM metallopeptidase domain 30) 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. This gene is testis-specific and contains a polymorphic region, resulting in isoforms with varying numbers of C-terminal repeats. [provided by RefSeq, Jul 2008]

ADAM30 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.002504617).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM30	NM_021794.4 link	c.1076T>C	p.Leu359Pro	missense_variant	Exon 1 of 1	ENST00000369400.2	NP_068566.2	Q9UKF2-1Q8TBZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM30	ENST00000369400.2 link	c.1076T>C	p.Leu359Pro	missense_variant	Exon 1 of 1	6	NM_021794.4	ENSP00000358407.1		Q9UKF2-1

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25710

AN:

152034

Hom.:

2998

Cov.:

show subpopulations

Gnomad AFR

AF:

0.326

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.0318

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.156

GnomAD2 exomes

AF:

0.125

AC:

31436

AN:

251408

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.337

Gnomad AMR exome

AF:

0.0888

Gnomad ASJ exome

AF:

0.0715

Gnomad EAS exome

AF:

0.0296

Gnomad FIN exome

AF:

0.143

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.116

AC:

169728

AN:

1461864

Hom.:

11537

Cov.:

AF XY:

0.118

AC XY:

85549

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.332

AC:

11129

AN:

33480

American (AMR)

AF:

0.0920

AC:

4115

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0684

AC:

1787

AN:

26132

East Asian (EAS)

AF:

0.0222

AC:

881

AN:

39700

South Asian (SAS)

AF:

0.195

AC:

16789

AN:

86256

European-Finnish (FIN)

AF:

0.145

AC:

7763

AN:

53420

Middle Eastern (MID)

AF:

0.0817

AC:

471

AN:

5768

European-Non Finnish (NFE)

AF:

0.107

AC:

119475

AN:

1111988

Other (OTH)

AF:

0.121

AC:

7318

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

9665

19330

28994

38659

48324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4524

9048

13572

18096

22620

<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:

0.169

AC:

25742

AN:

152152

Hom.:

3009

Cov.:

AF XY:

0.169

AC XY:

12588

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.326

AC:

13500

AN:

41456

American (AMR)

AF:

0.107

AC:

1634

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3470

East Asian (EAS)

AF:

0.0315

AC:

163

AN:

5180

South Asian (SAS)

AF:

0.199

AC:

956

AN:

4816

European-Finnish (FIN)

AF:

0.146

AC:

1545

AN:

10610

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7262

AN:

68002

Other (OTH)

AF:

0.156

AC:

329

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1015

2030

3045

4060

5075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.119

Hom.:

6178

Bravo

AF:

0.170

TwinsUK

AF:

0.103

AC:

383

ALSPAC

AF:

0.107

AC:

413

ESP6500AA

AF:

0.325

AC:

1431

ESP6500EA

AF:

0.104

AC:

896

ExAC

AF:

0.132

AC:

15974

Asia WGS

AF:

0.171

AC:

594

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.013

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.0071

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-2.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.25

REVEL

Benign

0.032

Sift

Benign

0.21

Sift4G

Benign

0.32

Polyphen

0.0020

Vest4

0.081

MPC

0.19

ClinPred

0.012

GERP RS

-9.3

Varity_R

0.065

gMVP

0.76

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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