rs16985437

Variant names:

• chr20-61683795-G-A
• rs16985437
• NM_001794.5:c.170-59768G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001794.5(CDH4):​c.170-59768G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 152,322 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.046 (302 hom., cov: 33)
• Consequence: CDH4 NM_001794.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.195
• Publications: 4 publications found

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]

CDH4 Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001794.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	NM_001794.5	MANE Select	c.170-59768G>A		intron	N/A	NP_001785.2
	CDH4	NM_001252338.2		c.59-59768G>A		intron	N/A	NP_001239267.1
	CDH4	NM_001252339.3		c.-53-59768G>A		intron	N/A	NP_001239268.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	ENST00000614565.5	TSL:1 MANE Select	c.170-59768G>A		intron	N/A	ENSP00000484928.1
	CDH4	ENST00000543233.2	TSL:2	c.-53-59768G>A		intron	N/A	ENSP00000443301.1
	CDH4	ENST00000611855.4	TSL:5	c.50-59768G>A		intron	N/A	ENSP00000480844.1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6935 AN: 152204 Hom.: 296 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0811

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0488

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0457 AC: 6966 AN: 152322 Hom.: 302 Cov.: 33 AF XY: 0.0458 AC XY: 3408 AN XY: 74486

African (AFR) AF: 0.103 AC: 4261 AN: 41562

American (AMR) AF: 0.0350 AC: 536 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.0802 AC: 387 AN: 4828

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1203 AN: 68038

Other (OTH) AF: 0.0526 AC: 111 AN: 2112

Alfa AF: 0.0340 Hom.: 26

Bravo AF: 0.0489

Asia WGS AF: 0.0470 AC: 164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.8
DANN	Benign	0.57
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16985437; hg19: chr20-60258851;