20-61773022-T-A

Variant names:

• chr20-61773022-T-A
• rs187067332
• NM_001794.5:c.416T>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001794.5(CDH4):​c.416T>A​(p.Val139Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,611,414 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 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: CDH4 NM_001794.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.11

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017797083).
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH4	NM_001794.5	c.416T>A	p.Val139Asp	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.416T>A	p.Val139Asp	missense_variant	Exon 4 of 16	1	NM_001794.5	ENSP00000484928.1
CDH4	ENST00000543233.2	c.194T>A	p.Val65Asp	missense_variant	Exon 3 of 15	2		ENSP00000443301.1
CDH4	ENST00000611855.4	c.134T>A	p.Val45Asp	missense_variant	Exon 3 of 15	5		ENSP00000480844.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000922 AC: 23 AN: 249494 Hom.: 0 AF XY: 0.0000963 AC XY: 13 AN XY: 134926

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000878

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: 0.000142

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000692 AC: 101 AN: 1459190 Hom.: 0 Cov.: 31 AF XY: 0.0000634 AC XY: 46 AN XY: 725548

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74426

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.416T>A (p.V139D) alteration is located in exon 4 (coding exon 4) of the CDH4 gene. This alteration results from a T to A substitution at nucleotide position 416, causing the valine (V) at amino acid position 139 to be replaced by an aspartic acid (D). 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	0.062
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0070
DANN	Benign	0.25
DEOGEN2	Benign	0.040	T;.;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.16	T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.61	.;.;N
REVEL	Benign	0.059
Sift	Benign	0.62	.;.;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.29
MVP		0.41
ClinPred		0.0036	T
GERP RS		-8.0
Varity_R		0.067
gMVP		0.42

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: rs187067332; hg19: chr20-60348078;