Variant 10-133263752-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001109.5(ADAM8):c.2333C>T(p.Thr778Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,540,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

ADAM8
NM_001109.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.777

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:

Genome browser will be placed here

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=0.0184685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM8	NM_001109.5 linkuse as main transcript	c.2333C>T	p.Thr778Met	missense_variant	22/23	ENST00000445355.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM8	ENST00000445355.8 linkuse as main transcript	c.2333C>T	p.Thr778Met	missense_variant	22/23	1	NM_001109.5	P2	P78325-1
ADAM8	ENST00000415217.7 linkuse as main transcript	c.2166C>T	p.Asn722=	synonymous_variant	21/22	1		A2	P78325-3
ADAM8	ENST00000485491.6 linkuse as main transcript	c.2125-519C>T		intron_variant		2			P78325-2
ADAM8	ENST00000559018.1 linkuse as main transcript	n.114C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.000155

AC:

AN:

142392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000526

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000680

Gnomad FIN

AF:

0.00174

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000301

AC:

AN:

189474

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

102562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000724

Gnomad SAS exome

AF:

0.000337

Gnomad FIN exome

AF:

0.00238

Gnomad NFE exome

AF:

0.0000475

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000141

AC:

197

AN:

1397760

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

107

AN XY:

692250

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000806

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000396

Gnomad4 FIN exome

AF:

0.00185

Gnomad4 NFE exome

AF:

0.0000603

Gnomad4 OTH exome

AF:

0.0000697

GnomAD4 genome

AF:

0.000154

AC:

AN:

142500

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

AN XY:

69384

show subpopulations

Gnomad4 AFR

AF:

0.0000525

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000679

Gnomad4 FIN

AF:

0.00174

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000364

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000158

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2022

The c.2333C>T (p.T778M) alteration is located in exon 22 (coding exon 22) of the ADAM8 gene. This alteration results from a C to T substitution at nucleotide position 2333, causing the threonine (T) at amino acid position 778 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.79

M_CAP

Benign

0.0034

MetaRNN

Benign

0.018

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

Sift

Uncertain

0.029

Sift4G

Benign

0.073

Polyphen

1.0

Vest4

0.38

MVP

0.48

MPC

0.57

GERP RS

1.5

Varity_R

0.034

gMVP

0.090

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over