Genetic Variant ADAM8:p.Ala820Ser (chr10-133263173-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001109.5(ADAM8):c.2458G>T(p.Ala820Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign 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. A820T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

ADAM8
NM_001109.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.249

Publications

0 publications found

Variant links:

Genes affected

ADAM8 (HGNC:215): (ADAM metallopeptidase domain 8) 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 may be involved in cell adhesion during neurodegeneration, and it is thought to be a target for allergic respiratory diseases, including asthma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2009]

ADAM8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022619039).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM8	NM_001109.5	MANE Select	c.2458G>T	p.Ala820Ser	missense	Exon 23 of 23	NP_001100.3	P78325-1
ADAM8	NM_001164490.2		c.2185G>T	p.Ala729Ser	missense	Exon 20 of 20	NP_001157962.1	P78325-2
ADAM8	NM_001164489.2		c.*62G>T		3_prime_UTR	Exon 22 of 22	NP_001157961.1	P78325-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM8	ENST00000445355.8	TSL:1 MANE Select	c.2458G>T	p.Ala820Ser	missense	Exon 23 of 23	ENSP00000453302.1	P78325-1
ADAM8	ENST00000415217.7	TSL:1	c.*62G>T		3_prime_UTR	Exon 22 of 22	ENSP00000453855.1	P78325-3
ADAM8	ENST00000897047.1		c.2452G>T	p.Ala818Ser	missense	Exon 23 of 23	ENSP00000567106.1

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.0000599

AC:

AN:

250544

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461532

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.000582

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111800

Other (OTH)

AF:

0.000282

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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

AF:

0.000368

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41594

American (AMR)

AF:

0.00281

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000801

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.3

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.049

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.46

M_CAP

Benign

0.00072

MetaRNN

Benign

0.023

MutationAssessor

Benign

0.69

PhyloP100

0.25

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.54

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.082

MVP

0.39

MPC

0.16

GERP RS

-0.70

Varity_R

0.10

gMVP

0.056

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over