NM_153000.5:c.774+4763G>T

Variant names:

• chr18-10476824-G-T
• rs547668
• NM_153000.5:c.774+4763G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• Publications: 10 publications found

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

ENSG00000301982 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153000.5. 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
	APCDD1	NM_153000.5	MANE Select	c.774+4763G>T		intron	N/A	NP_694545.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APCDD1	ENST00000355285.10	TSL:1 MANE Select	c.774+4763G>T		intron	N/A	ENSP00000347433.4
	APCDD1	ENST00000584596.2	TSL:3	c.*482G>T		3_prime_UTR	Exon 2 of 2	ENSP00000476491.1
	APCDD1	ENST00000578882.1	TSL:3	c.453+5084G>T		intron	N/A	ENSP00000463104.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36549 AN: 152088 Hom.: 5961 Cov.: 33

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: 5 AN: 18 Hom.: 2 Cov.: 0 AF XY: 0.357 AC XY: 5 AN XY: 14

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.286 AC: 4 AN: 14

Other (OTH) AF: 0.250 AC: 1 AN: 4

⚠️ 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.

GnomAD4 genome AF: 0.240 AC: 36592 AN: 152206 Hom.: 5968 Cov.: 33 AF XY: 0.236 AC XY: 17584 AN XY: 74448

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: 70 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10381 AN: 68004

Other (OTH) AF: 0.203 AC: 429 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.28
DANN	Benign	0.58
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs547668; hg19: chr18-10476821;