16-68698554-G-T

Position:

• chr16-68698554-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001793.6(CDH3):​c.*154G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 657,706 control chromosomes in the GnomAD database, including 241,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55271 hom., cov: 31)
  • Exomes 𝑓: 0.86 (186651 hom.)
• Consequence: CDH3 NM_001793.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.64

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-68698554-G-T is Benign according to our data. Variant chr16-68698554-G-T is described in ClinVar as [Benign]. Clinvar id is 320258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH3	NM_001793.6	c.*154G>T		3_prime_UTR_variant	16/16	ENST00000264012.9	NP_001784.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH3	ENST00000264012.9	c.*154G>T		3_prime_UTR_variant	16/16	1	NM_001793.6	ENSP00000264012.4

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129396 AN: 151986 Hom.: 55242 Cov.: 31

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.886

Gnomad OTH AF: 0.867

GnomAD4 exome AF: 0.857 AC: 433371 AN: 505602 Hom.: 186651 Cov.: 6 AF XY: 0.854 AC XY: 226789 AN XY: 265612

Gnomad4 AFR exome AF: 0.821

Gnomad4 AMR exome AF: 0.776

Gnomad4 ASJ exome AF: 0.933

Gnomad4 EAS exome AF: 0.763

Gnomad4 SAS exome AF: 0.776

Gnomad4 FIN exome AF: 0.837

Gnomad4 NFE exome AF: 0.885

Gnomad4 OTH exome AF: 0.868

GnomAD4 genome AF: 0.851 AC: 129478 AN: 152104 Hom.: 55271 Cov.: 31 AF XY: 0.845 AC XY: 62861 AN XY: 74348

Gnomad4 AFR AF: 0.823

Gnomad4 AMR AF: 0.817

Gnomad4 ASJ AF: 0.935

Gnomad4 EAS AF: 0.773

Gnomad4 SAS AF: 0.780

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.886

Gnomad4 OTH AF: 0.864

Alfa AF: 0.877 Hom.: 59340

Bravo AF: 0.848

Asia WGS AF: 0.786 AC: 2736 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

EEM syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.41
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1886699; hg19: chr16-68732457;