chr10-133263747-C-T

Position:

• chr10-133263747-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001109.5(ADAM8):​c.2338G>A​(p.Ala780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,569,702 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A780P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: ADAM8 NM_001109.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.520

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0060773194).
• BP6: Variant 10-133263747-C-T is Benign according to our data. Variant chr10-133263747-C-T is described in ClinVar as [Benign]. Clinvar id is 786585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM8	NM_001109.5	c.2338G>A	p.Ala780Thr	missense_variant	22/23	ENST00000445355.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM8	ENST00000445355.8	c.2338G>A	p.Ala780Thr	missense_variant	22/23	1	NM_001109.5	P2
ADAM8	ENST00000415217.7	c.2171G>A	p.Arg724His	missense_variant	21/22	1		A2
ADAM8	ENST00000485491.6	c.2125-514G>A		intron_variant		2
ADAM8	ENST00000559018.1	n.119G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152174 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.000103

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000505 AC: 96 AN: 189946 Hom.: 0 AF XY: 0.000340 AC XY: 35 AN XY: 102798

Gnomad AFR exome AF: 0.00791

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000728

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.000216

GnomAD4 exome AF: 0.000190 AC: 269 AN: 1417410 Hom.: 1 Cov.: 37 AF XY: 0.000154 AC XY: 108 AN XY: 702160

Gnomad4 AFR exome AF: 0.00659

Gnomad4 AMR exome AF: 0.000260

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000811

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.000581

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152292 Hom.: 0 Cov.: 36 AF XY: 0.00201 AC XY: 150 AN XY: 74456

Gnomad4 AFR AF: 0.00756

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000113 Hom.: 0

Bravo AF: 0.00253

ESP6500AA AF: 0.00682 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000655 AC: 79

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.89
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0061	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.55	N
Sift	Benign	0.42	T
Sift4G	Benign	0.77	T
Polyphen		0.10	B
Vest4		0.10
MVP		0.48
MPC		0.12
GERP RS		-0.75
Varity_R		0.025
gMVP		0.092

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs61733287; hg19: chr10-135077251; COSMIC: COSV99065679;