16-68698554-G-T

Variant names:

• chr16-68698554-G-T
• rs1886699
• NM_001793.6:c.*154G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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 Gene-Disease associations (from GenCC):

• EEM syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital hypotrichosis with juvenile macular dystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001793.6. 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
	CDH3	NM_001793.6	MANE Select	c.*154G>T		3_prime_UTR	Exon 16 of 16	NP_001784.2
	CDH3	NM_001317195.3		c.*387G>T		3_prime_UTR	Exon 16 of 16	NP_001304124.1
	CDH3	NM_001317196.2		c.*154G>T		3_prime_UTR	Exon 15 of 15	NP_001304125.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH3	ENST00000264012.9	TSL:1 MANE Select	c.*154G>T		3_prime_UTR	Exon 16 of 16	ENSP00000264012.4
	CDH3	ENST00000429102.6	TSL:1	c.*387G>T		3_prime_UTR	Exon 16 of 16	ENSP00000398485.2
	CDH3	ENST00000542274.5	TSL:2	n.*2382G>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000464021.1

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

African (AFR) AF: 0.821 AC: 11281 AN: 13736

American (AMR) AF: 0.776 AC: 17587 AN: 22658

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 13744 AN: 14730

East Asian (EAS) AF: 0.763 AC: 24108 AN: 31608

South Asian (SAS) AF: 0.776 AC: 37719 AN: 48612

European-Finnish (FIN) AF: 0.837 AC: 30438 AN: 36372

Middle Eastern (MID) AF: 0.865 AC: 1838 AN: 2126

European-Non Finnish (NFE) AF: 0.885 AC: 272361 AN: 307782

Other (OTH) AF: 0.868 AC: 24295 AN: 27978

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

African (AFR) AF: 0.823 AC: 34150 AN: 41508

American (AMR) AF: 0.817 AC: 12473 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.935 AC: 3243 AN: 3470

East Asian (EAS) AF: 0.773 AC: 3985 AN: 5154

South Asian (SAS) AF: 0.780 AC: 3761 AN: 4822

European-Finnish (FIN) AF: 0.824 AC: 8707 AN: 10562

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.886 AC: 60239 AN: 68000

Other (OTH) AF: 0.864 AC: 1826 AN: 2114

Alfa AF: 0.873 Hom.: 76325

Bravo AF: 0.848

Asia WGS AF: 0.786 AC: 2736 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	EEM syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.41
DANN	Benign	0.42
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1886699; hg19: chr16-68732457;