10-133263173-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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. 12/19 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

2
1
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.249
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.022619039).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAM8NM_001109.5 linkc.2458G>T p.Ala820Ser missense_variant Exon 23 of 23 ENST00000445355.8 NP_001100.3 P78325-1Q14C66

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAM8ENST00000445355.8 linkc.2458G>T p.Ala820Ser missense_variant Exon 23 of 23 1 NM_001109.5 ENSP00000453302.1 P78325-1
ADAM8ENST00000415217 linkc.*62G>T 3_prime_UTR_variant Exon 22 of 22 1 ENSP00000453855.1 P78325-3
ADAM8ENST00000485491.6 linkc.2185G>T p.Ala729Ser missense_variant Exon 20 of 20 2 ENSP00000453043.1 P78325-2
ADAM8ENST00000559018.1 linkn.239G>T non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.000374
AC:
57
AN:
152248
Hom.:
0
Cov.:
35
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
GnomAD3 exomes
AF:
0.0000599
AC:
15
AN:
250544
Hom.:
0
AF XY:
0.0000590
AC XY:
8
AN XY:
135500
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 SAS 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:
50
AN:
1461532
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
727062
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.000582
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.000282
GnomAD4 genome
AF:
0.000368
AC:
56
AN:
152366
Hom.:
0
Cov.:
35
AF XY:
0.000282
AC XY:
21
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00281
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00425
Alfa
AF:
0.000203
Hom.:
0
Bravo
AF:
0.000801
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000577
AC:
2
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
-0.48
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
9.3
DANN
Uncertain
0.97
DEOGEN2
Benign
0.049
T;.
FATHMM_MKL
Benign
0.076
N
LIST_S2
Benign
0.46
T;T
M_CAP
Benign
0.00072
T
MetaRNN
Benign
0.023
T;T
MutationAssessor
Benign
0.69
N;.
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.54
N;N
Sift
Pathogenic
0.0
D;T
Sift4G
Pathogenic
0.0
D;T
Vest4
0.082
MVP
0.39
MPC
0.16
GERP RS
-0.70
Varity_R
0.10
gMVP
0.056

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.

Other links and lift over

dbSNP: rs561363568; hg19: chr10-135076677; API