Genetic Variant APCDD1:c.774+4763G>T (chr18-10476824-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_153000.5(APCDD1):c.774+4763G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 152,224 control chromosomes in the GnomAD database, including 5,970 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 0.24 ( 5968 hom., cov: 33)

Exomes 𝑓: 0.28 ( 2 hom. )

Consequence

APCDD1
NM_153000.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.17

Publications

10 publications found

Variant links:

Genes affected

APCDD1 (HGNC:15718): (APC down-regulated 1) This locus encodes an inhibitor of the Wnt signaling pathway. Mutations at this locus have been associated with hereditary hypotrichosis simplex. Increased expression of this gene may also be associated with colorectal carcinogenesis.[provided by RefSeq, Sep 2010]

APCDD1 Gene-Disease associations (from GenCC):

hypotrichosis 1
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
hypotrichosis simplex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

APCDD1 links:

ENSG00000301982 (HGNC:):

ENSG00000301982 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APCDD1	NM_153000.5 link	c.774+4763G>T		intron_variant	Intron 3 of 4	ENST00000355285.10	NP_694545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APCDD1	ENST00000355285.10 link	c.774+4763G>T		intron_variant	Intron 3 of 4	1	NM_153000.5	ENSP00000347433.4

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36549

AN:

152088

Hom.:

5961

Cov.:

show subpopulations

Gnomad AFR

AF:

0.465

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.153

Gnomad OTH

AF:

0.205

GnomAD4 exome

AF:

0.278

AC:

AN:

Hom.:

Cov.:

AF XY:

0.357

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.286

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.240

AC:

36592

AN:

152206

Hom.:

5968

Cov.:

AF XY:

0.236

AC XY:

17584

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.465

AC:

19293

AN:

41486

American (AMR)

AF:

0.183

AC:

2801

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

448

AN:

3470

East Asian (EAS)

AF:

0.150

AC:

776

AN:

5180

South Asian (SAS)

AF:

0.171

AC:

824

AN:

4826

European-Finnish (FIN)

AF:

0.138

AC:

1465

AN:

10618

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.153

AC:

10381

AN:

68004

Other (OTH)

AF:

0.203

AC:

429

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1318

2637

3955

5274

6592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.178

Hom.:

4395

Bravo

AF:

0.255

Asia WGS

AF:

0.169

AC:

590

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.28

(source)

DANN

Benign

0.58

PhyloP100

-2.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over