Variant 8-39610636-C-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 ENST00000265707.10(ADAM18):c.452C>A(p.Ser151Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000838 in 1,612,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

ADAM18
ENST00000265707.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.202

Variant links:

Genes affected

ADAM18 (HGNC:196): (ADAM metallopeptidase domain 18) 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 biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature sperm surface protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAM18 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=0.033640414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAM18	NM_014237.3 linkuse as main transcript	c.452C>A	p.Ser151Tyr	missense_variant	6/20	ENST00000265707.10	NP_055052.1
ADAM18	NM_001320313.2 linkuse as main transcript	c.452C>A	p.Ser151Tyr	missense_variant	6/19		NP_001307242.1
ADAM18	NM_001190956.2 linkuse as main transcript	c.452C>A	p.Ser151Tyr	missense_variant	6/6		NP_001177885.1
ADAM18	NR_135201.2 linkuse as main transcript	n.399+1075C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM18	ENST00000265707.10 linkuse as main transcript	c.452C>A	p.Ser151Tyr	missense_variant	6/20	1	NM_014237.3	ENSP00000265707	P1	Q9Y3Q7-1

Frequencies

GnomAD3 genomes

AF:

0.000507

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000957

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000436

AC:

109

AN:

249968

Hom.:

AF XY:

0.000459

AC XY:

AN XY:

135152

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000872

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:

0.000887

Gnomad OTH exome

AF:

0.000659

GnomAD4 exome

AF:

0.000873

AC:

1275

AN:

1460646

Hom.:

Cov.:

AF XY:

0.000800

AC XY:

581

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00109

Gnomad4 OTH exome

AF:

0.000845

GnomAD4 genome

AF:

0.000506

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000957

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000727

Hom.:

Bravo

AF:

0.000521

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000546

EpiControl

AF:

0.000890

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

Sep 17, 2021

The c.452C>A (p.S151Y) alteration is located in exon 6 (coding exon 6) of the ADAM18 gene. This alteration results from a C to A substitution at nucleotide position 452, causing the serine (S) at amino acid position 151 to be replaced by a tyrosine (Y). 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

0.099

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.10

DEOGEN2

Benign

0.038

T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.14

M_CAP

Benign

0.0035

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Benign

0.047

Sift

Benign

0.33

T;T;T

Sift4G

Benign

1.0

T;T;D

Polyphen

0.24

B;B;.

Vest4

0.33

MVP

0.41

MPC

0.057

ClinPred

0.058

GERP RS

3.7

Varity_R

0.11

gMVP

0.39

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.

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