Variant 8-39584674-G-C 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_014237.3(ADAM18):c.52G>C(p.Glu18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ADAM18
NM_014237.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0570

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:

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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=0.031926453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAM18	NM_014237.3 linkuse as main transcript	c.52G>C	p.Glu18Gln	missense_variant	1/20	ENST00000265707.10	NP_055052.1
ADAM18	NM_001320313.2 linkuse as main transcript	c.52G>C	p.Glu18Gln	missense_variant	1/19		NP_001307242.1
ADAM18	NM_001190956.2 linkuse as main transcript	c.52G>C	p.Glu18Gln	missense_variant	1/6		NP_001177885.1
ADAM18	NR_135201.2 linkuse as main transcript	n.107G>C		non_coding_transcript_exon_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM18	ENST00000265707.10 linkuse as main transcript	c.52G>C	p.Glu18Gln	missense_variant	1/20	1	NM_014237.3	ENSP00000265707	P1	Q9Y3Q7-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250588

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460802

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000144

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000457

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:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Dec 20, 2021

The c.52G>C (p.E18Q) alteration is located in exon 1 (coding exon 1) of the ADAM18 gene. This alteration results from a G to C substitution at nucleotide position 52, causing the glutamic acid (E) at amino acid position 18 to be replaced by a glutamine (Q). 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

0.075

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.4

DANN

Benign

0.71

DEOGEN2

Benign

0.00041

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00064

M_CAP

Benign

0.0022

MetaRNN

Benign

0.032

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.81

N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.29

N;N;N

REVEL

Benign

0.011

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.086

MVP

0.23

MPC

0.017

ClinPred

0.016

GERP RS

-1.1

Varity_R

0.044

gMVP

0.51

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