14-70522769-G-C

Position:

• chr14-70522769-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003814.5(ADAM20):​c.1989C>G​(p.Cys663Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM20 NM_003814.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0670

Genes affected

ADAM20 (HGNC:199): (ADAM metallopeptidase domain 20) 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 biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The expression of this gene is testis-specific. [provided by RefSeq, Jul 2008]

ENSG00000257759 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM20	NM_003814.5	c.1989C>G	p.Cys663Trp	missense_variant	2/2	ENST00000256389.5	NP_003805.4
ADAM20	XM_005268151.4	c.2139C>G	p.Cys713Trp	missense_variant	2/2		XP_005268208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM20	ENST00000256389.5	c.1989C>G	p.Cys663Trp	missense_variant	2/2	1	NM_003814.5	ENSP00000256389.3
ADAM20	ENST00000652041.1	c.2139C>G	p.Cys713Trp	missense_variant	2/2			ENSP00000498512.1
ENSG00000257759	ENST00000556646.1	n.183+24513C>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.2139C>G (p.C713W) alteration is located in exon 2 (coding exon 1) of the ADAM20 gene. This alteration results from a C to G substitution at nucleotide position 2139, causing the cysteine (C) at amino acid position 713 to be replaced by a tryptophan (W). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	18
DANN	Benign	0.95
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.040	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0030	D
Vest4		0.47
MVP		0.48
MPC		0.25
ClinPred		1.0	D
GERP RS		-4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-70989486;