Variant 8-39648422-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014237.3(ADAM18):c.1125A>T(p.Lys375Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,850 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADAM18
NM_014237.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0610

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAM18	NM_014237.3 linkuse as main transcript	c.1125A>T	p.Lys375Asn	missense_variant	12/20	ENST00000265707.10	NP_055052.1
ADAM18	NM_001320313.2 linkuse as main transcript	c.1053A>T	p.Lys351Asn	missense_variant	11/19		NP_001307242.1
ADAM18	NR_135201.2 linkuse as main transcript	n.923+2948A>T		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.1125A>T	p.Lys375Asn	missense_variant	12/20	1	NM_014237.3	ENSP00000265707	P1	Q9Y3Q7-1
ADAM18	ENST00000379866.5 linkuse as main transcript	c.1053A>T	p.Lys351Asn	missense_variant	11/19	1		ENSP00000369195		Q9Y3Q7-2
ADAM18	ENST00000520087.5 linkuse as main transcript	c.*520+2948A>T		intron_variant, NMD_transcript_variant		1		ENSP00000428083

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 16, 2022

The c.1125A>T (p.K375N) alteration is located in exon 12 (coding exon 12) of the ADAM18 gene. This alteration results from a A to T substitution at nucleotide position 1125, causing the lysine (K) at amino acid position 375 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0065

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.044

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.097

Sift

Benign

0.062

T;T

Sift4G

Benign

0.073

T;T

Polyphen

0.068

B;B

Vest4

0.14

MutPred

0.53

Loss of methylation at K375 (P = 0.0071);.;

MVP

0.57

MPC

0.036

ClinPred

0.15

GERP RS

1.6

Varity_R

0.13

gMVP

0.58

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