20-61773025-T-G

Variant names:

• chr20-61773025-T-G
• NM_001794.5:c.419T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001794.5(CDH4):​c.419T>G​(p.Val140Gly) 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 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: not found (cov: 33)
• Consequence: CDH4 NM_001794.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.287

Genes affected

CDH4 (HGNC:1763): (cadherin 4) This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Based on studies in chicken and mouse, this cadherin is thought to play an important role during brain segmentation and neuronal outgrowth. In addition, a role in kidney and muscle development is indicated. Of particular interest are studies showing stable cis-heterodimers of cadherins 2 and 4 in cotransfected cell lines. Previously thought to interact in an exclusively homophilic manner, this is the first evidence of cadherin heterodimerization. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

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=0.06834945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH4	NM_001794.5	c.419T>G	p.Val140Gly	missense_variant	Exon 4 of 16	ENST00000614565.5	NP_001785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH4	ENST00000614565.5	c.419T>G	p.Val140Gly	missense_variant	Exon 4 of 16	1	NM_001794.5	ENSP00000484928.1
CDH4	ENST00000543233.2	c.197T>G	p.Val66Gly	missense_variant	Exon 3 of 15	2		ENSP00000443301.1
CDH4	ENST00000611855.4	c.137T>G	p.Val46Gly	missense_variant	Exon 3 of 15	5		ENSP00000480844.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.419T>G (p.V140G) alteration is located in exon 4 (coding exon 4) of the CDH4 gene. This alteration results from a T to G substitution at nucleotide position 419, causing the valine (V) at amino acid position 140 to be replaced by a glycine (G). 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	0.071
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.2
DANN	Benign	0.34
DEOGEN2	Benign	0.099	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.26	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.15	.;.;N
REVEL	Benign	0.065
Sift	Benign	0.47	.;.;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.11
MutPred		0.32		Loss of sheet (P = 0.0126);.;.;
MVP		0.27
ClinPred		0.20	T
GERP RS		-5.2
Varity_R		0.039
gMVP		0.39

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: chr20-60348081;