Genetic Variant NM_001793.6:c.720G>A (chr16-68679827-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001793.6(CDH3):c.720G>A(p.Thr240Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 1,610,936 control chromosomes in the GnomAD database, including 307,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 29939 hom., cov: 30)

Exomes 𝑓: 0.61 ( 277357 hom. )

Consequence

CDH3
NM_001793.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.96

Publications

32 publications found

Variant links:

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)

CDH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 16-68679827-G-A is Benign according to our data. Variant chr16-68679827-G-A is described in ClinVar as Benign. ClinVar VariationId is 320229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.96 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH3	NM_001793.6	MANE Select	c.720G>A	p.Thr240Thr	synonymous	Exon 7 of 16	NP_001784.2
CDH3	NM_001317195.3		c.720G>A	p.Thr240Thr	synonymous	Exon 7 of 16	NP_001304124.1
CDH3	NM_001317196.2		c.555G>A	p.Thr185Thr	synonymous	Exon 6 of 15	NP_001304125.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH3	ENST00000264012.9	TSL:1 MANE Select	c.720G>A	p.Thr240Thr	synonymous	Exon 7 of 16	ENSP00000264012.4
CDH3	ENST00000429102.6	TSL:1	c.720G>A	p.Thr240Thr	synonymous	Exon 7 of 16	ENSP00000398485.2
CDH3	ENST00000914963.1		c.720G>A	p.Thr240Thr	synonymous	Exon 7 of 16	ENSP00000585022.1

Frequencies

GnomAD3 genomes

AF:

0.627

AC:

94977

AN:

151494

Hom.:

29909

Cov.:

show subpopulations

Gnomad AFR

AF:

0.674

Gnomad AMI

AF:

0.719

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.572

Gnomad EAS

AF:

0.628

Gnomad SAS

AF:

0.546

Gnomad FIN

AF:

0.610

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.627

Gnomad OTH

AF:

0.618

GnomAD2 exomes

AF:

0.589

AC:

148094

AN:

251386

AF XY:

0.590

show subpopulations

Gnomad AFR exome

AF:

0.675

Gnomad AMR exome

AF:

0.473

Gnomad ASJ exome

AF:

0.579

Gnomad EAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.604

Gnomad NFE exome

AF:

0.620

Gnomad OTH exome

AF:

0.590

GnomAD4 exome

AF:

0.615

AC:

897082

AN:

1459324

Hom.:

277357

Cov.:

AF XY:

0.612

AC XY:

444731

AN XY:

726122

show subpopulations

African (AFR)

AF:

0.669

AC:

22380

AN:

33450

American (AMR)

AF:

0.484

AC:

21646

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.580

AC:

15149

AN:

26120

East Asian (EAS)

AF:

0.633

AC:

25102

AN:

39670

South Asian (SAS)

AF:

0.542

AC:

46741

AN:

86208

European-Finnish (FIN)

AF:

0.612

AC:

32649

AN:

53384

Middle Eastern (MID)

AF:

0.552

AC:

3182

AN:

5760

European-Non Finnish (NFE)

AF:

0.625

AC:

693317

AN:

1109694

Other (OTH)

AF:

0.612

AC:

36916

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

17246

34492

51739

68985

86231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18496

36992

55488

73984

92480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.627

AC:

95063

AN:

151612

Hom.:

29939

Cov.:

AF XY:

0.622

AC XY:

46080

AN XY:

74064

show subpopulations

African (AFR)

AF:

0.674

AC:

27848

AN:

41318

American (AMR)

AF:

0.543

AC:

8266

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.572

AC:

1983

AN:

3466

East Asian (EAS)

AF:

0.627

AC:

3220

AN:

5132

South Asian (SAS)

AF:

0.546

AC:

2610

AN:

4784

European-Finnish (FIN)

AF:

0.610

AC:

6400

AN:

10490

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.627

AC:

42594

AN:

67898

Other (OTH)

AF:

0.619

AC:

1300

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1805

3611

5416

7222

9027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

784

1568

2352

3136

3920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.618

Hom.:

52245

Bravo

AF:

0.624

Asia WGS

AF:

0.554

AC:

1929

AN:

3476

EpiCase

AF:

0.621

EpiControl

AF:

0.618

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

EEM syndrome (2)

Congenital hypotrichosis with juvenile macular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.28

(source)

DANN

Benign

0.43

PhyloP100

-4.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over