8-39610551-A-C

Position:

• chr8-39610551-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014237.3(ADAM18):​c.367A>C​(p.Ile123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,607,278 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (12 hom.)
• Consequence: ADAM18 NM_014237.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.316

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068491697).
• BP6: Variant 8-39610551-A-C is Benign according to our data. Variant chr8-39610551-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2658565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM18	NM_014237.3	c.367A>C	p.Ile123Leu	missense_variant	6/20	ENST00000265707.10	NP_055052.1
ADAM18	NM_001320313.2	c.367A>C	p.Ile123Leu	missense_variant	6/19		NP_001307242.1
ADAM18	NM_001190956.2	c.367A>C	p.Ile123Leu	missense_variant	6/6		NP_001177885.1
ADAM18	NR_135201.2	n.399+990A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM18	ENST00000265707.10	c.367A>C	p.Ile123Leu	missense_variant	6/20	1	NM_014237.3	ENSP00000265707	P1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152122 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00799

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00200 AC: 492 AN: 245768 Hom.: 3 AF XY: 0.00168 AC XY: 224 AN XY: 133208

Gnomad AFR exome AF: 0.00741

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.00403

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00388

GnomAD4 exome AF: 0.00125 AC: 1816 AN: 1455038 Hom.: 12 Cov.: 30 AF XY: 0.00121 AC XY: 878 AN XY: 723652

Gnomad4 AFR exome AF: 0.00773

Gnomad4 AMR exome AF: 0.00576

Gnomad4 ASJ exome AF: 0.00438

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000189

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000864

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152240 Hom.: 4 Cov.: 32 AF XY: 0.00445 AC XY: 331 AN XY: 74454

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00540

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00706 AC: 31

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

ADAM18: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.5
DANN	Benign	0.88
DEOGEN2	Benign	0.0044	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.067	N
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.070
Sift	Uncertain	0.027	D;D;D
Sift4G	Uncertain	0.041	D;D;D
Polyphen		0.16	B;B;.
Vest4		0.31
MVP		0.10
MPC		0.020
ClinPred		0.0044	T
GERP RS		-3.8
Varity_R		0.13
gMVP		0.34

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

Other links and lift over

dbSNP: rs139114737; hg19: chr8-39468070;