8-39637614-T-A

Position:

chr8-39637614-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014237.3(ADAM18):c.738T>A(p.Ser246Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,612,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ADAM18
NM_014237.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.62

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11645639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAM18	NM_014237.3 linkuse as main transcript	c.738T>A	p.Ser246Arg	missense_variant	9/20	ENST00000265707.10	NP_055052.1
ADAM18	NM_001320313.2 linkuse as main transcript	c.666T>A	p.Ser222Arg	missense_variant	8/19		NP_001307242.1
ADAM18	NR_135201.2 linkuse as main transcript	n.615T>A		non_coding_transcript_exon_variant	8/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM18	ENST00000265707.10 linkuse as main transcript	c.738T>A	p.Ser246Arg	missense_variant	9/20	1	NM_014237.3	ENSP00000265707	P1	Q9Y3Q7-1
ADAM18	ENST00000379866.5 linkuse as main transcript	c.666T>A	p.Ser222Arg	missense_variant	8/19	1		ENSP00000369195		Q9Y3Q7-2
ADAM18	ENST00000520087.5 linkuse as main transcript	c.*212T>A		3_prime_UTR_variant, NMD_transcript_variant	8/18	1		ENSP00000428083

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250700

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1460732

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.0000593

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

Nov 18, 2022

The c.738T>A (p.S246R) alteration is located in exon 9 (coding exon 9) of the ADAM18 gene. This alteration results from a T to A substitution at nucleotide position 738, causing the serine (S) at amino acid position 246 to be replaced by an arginine (R). 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

0.13

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.083

DANN

Benign

0.83

DEOGEN2

Benign

0.0083

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.011

M_CAP

Benign

0.014

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.087

Sift

Uncertain

0.025

D;T

Sift4G

Benign

0.18

T;T

Polyphen

0.29

B;B

Vest4

0.28

MutPred

0.48

Loss of glycosylation at S246 (P = 0.0134);.;

MVP

0.28

MPC

0.024

ClinPred

0.077

GERP RS

-10

Varity_R

0.16

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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