10-133267956-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The ENST00000415217.7(ADAM8):​c.2059G>A​(p.Gly687Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,260,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ADAM8
ENST00000415217.7 missense

Scores

1
10

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061580032).
BP6
Variant 10-133267956-C-T is Benign according to our data. Variant chr10-133267956-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3146127.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADAM8NM_001109.5 linkuse as main transcriptc.2226G>A p.Ser742= synonymous_variant 20/23 ENST00000445355.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADAM8ENST00000415217.7 linkuse as main transcriptc.2059G>A p.Gly687Ser missense_variant 19/221 A2P78325-3
ADAM8ENST00000445355.8 linkuse as main transcriptc.2226G>A p.Ser742= synonymous_variant 20/231 NM_001109.5 P2P78325-1
ADAM8ENST00000485491.6 linkuse as main transcriptc.2031G>A p.Ser677= synonymous_variant 18/202 P78325-2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000441
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.0000363
AC:
1
AN:
27578
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
14662
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000905
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000162
AC:
18
AN:
1108470
Hom.:
0
Cov.:
31
AF XY:
0.0000133
AC XY:
7
AN XY:
524974
show subpopulations
Gnomad4 AFR exome
AF:
0.000170
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000365
Gnomad4 SAS exome
AF:
0.0000479
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000452
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000946
Bravo
AF:
0.0000529
ExAC
AF:
0.00000988
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 22, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
0.25
DANN
Benign
0.95
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.38
T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.062
T
MutationTaster
Benign
1.0
N;N;N
PROVEAN
Benign
0.67
N
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.48
T
Vest4
0.14
MVP
0.51
GERP RS
-3.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs374536208; hg19: chr10-135081460; API