16-68645113-C-T

Variant names:

• chr16-68645113-C-T
• rs182969772
• ENST00000429102.6:c.-267C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000429102.6(CDH3):​c.-267C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 595,258 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (45 hom.)
• Consequence: CDH3 ENST00000429102.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0150
• Publications: 1 publications found

Genes affected

CDH3 (HGNC:1762): (cadherin 3) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant expression of this protein is observed in cervical adenocarcinomas. Mutations in this gene are associated with hypotrichosis with juvenile macular dystrophy and ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS). [provided by RefSeq, Nov 2015]

CDH3-AS1 (HGNC:56084): (CDH3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00527 (803/152288) while in subpopulation NFE AF = 0.000853 (58/68022). AF 95% confidence interval is 0.000677. There are 26 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000429102.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH3-AS1	NR_186394.1		n.850G>A		non_coding_transcript_exon	Exon 2 of 2
	CDH3	NM_001793.6	MANE Select	c.-267C>T		upstream_gene	N/A	NP_001784.2
	CDH3	NM_001317195.3		c.-267C>T		upstream_gene	N/A	NP_001304124.1	P22223-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH3	ENST00000429102.6	TSL:1	c.-267C>T		5_prime_UTR	Exon 1 of 16	ENSP00000398485.2	P22223-2
	CDH3-AS1	ENST00000562172.2	TSL:3	n.817G>A		non_coding_transcript_exon	Exon 2 of 2
	CDH3	ENST00000565453.1	TSL:4	n.327C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 803 AN: 152170 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0687

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00426 AC: 1885 AN: 442970 Hom.: 45 Cov.: 0 AF XY: 0.00371 AC XY: 869 AN XY: 234296

African (AFR) AF: 0.00 AC: 0 AN: 12216

American (AMR) AF: 0.000270 AC: 5 AN: 18492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13470

East Asian (EAS) AF: 0.0000326 AC: 1 AN: 30646

South Asian (SAS) AF: 0.00 AC: 0 AN: 45696

European-Finnish (FIN) AF: 0.0558 AC: 1606 AN: 28796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1948

European-Non Finnish (NFE) AF: 0.000710 AC: 189 AN: 266082

Other (OTH) AF: 0.00328 AC: 84 AN: 25624

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152288 Hom.: 26 Cov.: 33 AF XY: 0.00779 AC XY: 580 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0687 AC: 728 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000801 Hom.: 1

Bravo AF: 0.000446

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	EEM syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.1
DANN	Benign	0.62
PhyloP100		-0.015
PromoterAI		-0.0014	Neutral
Mutation Taster		=300/0	polymorphism

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: rs182969772; hg19: chr16-68679016;