Genetic Variant NM_003817.4:c.1475G>C (chr8-24492021-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003817.4(ADAM7):c.1475G>C(p.Cys492Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C492Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ADAM7
NM_003817.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.93

Publications

0 publications found

Variant links:

Genes affected

ADAM7 (HGNC:214): (ADAM metallopeptidase domain 7) This gene encodes a member of the ADAMs family of zinc proteases. These transmembrane proteins play roles in multiple processes including cell signaling, adhesion and migration. The encoded protein lacks protease activity and may play roles in protein-protein interactions and cell adhesion processes including sperm-egg fusion. Mutations in this gene may be involved in the progression of melanoma. [provided by RefSeq, Oct 2011]

ADAM7 links:

ADAM7-AS2 (HGNC:56153): (ADAM7 antisense RNA 2)

ADAM7-AS2 links:

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

ADAM7-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003817.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM7	NM_003817.4	MANE Select	c.1475G>C	p.Cys492Ser	missense	Exon 14 of 22	NP_003808.2	A0A384MTL6
ADAM7-AS2	NR_125809.1		n.586C>G		non_coding_transcript_exon	Exon 4 of 5
ADAM7-AS1	NR_125808.1		n.79+56519C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM7	ENST00000175238.10	TSL:1 MANE Select	c.1475G>C	p.Cys492Ser	missense	Exon 14 of 22	ENSP00000175238.5	Q9H2U9-1
ADAM7	ENST00000520720.1	TSL:1	c.791G>C	p.Cys264Ser	missense	Exon 8 of 15	ENSP00000430400.1	E5RK87
ADAM7	ENST00000380789.5	TSL:5	c.1475G>C	p.Cys492Ser	missense	Exon 14 of 23	ENSP00000370166.1	C9JK28

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111868

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

4.5

PhyloP100

7.9

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-9.6

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.93

MutPred

0.94

Loss of catalytic residue at P491 (P = 0.0079)

MVP

0.89

MPC

0.35

ClinPred

1.0

GERP RS

6.0

Varity_R

0.99

gMVP

0.98

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over