18-10454963-C-G

Variant names:

• chr18-10454963-C-G
• rs28769876
• NM_153000.5:c.-19C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153000.5(APCDD1):​c.-19C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 151,982 control chromosomes in the GnomAD database, including 75,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75990 hom., cov: 32)
  • Exomes 𝑓: 1.0 (690023 hom.)
  • Failed GnomAD Quality Control
• Consequence: APCDD1 NM_153000.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.60
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 18-10454963-C-G is Benign according to our data. Variant chr18-10454963-C-G is described in ClinVar as Benign. ClinVar VariationId is 1230499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APCDD1	NM_153000.5	MANE Select	c.-19C>G		5_prime_UTR	Exon 1 of 5	NP_694545.1	Q8J025

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APCDD1	ENST00000355285.10	TSL:1 MANE Select	c.-19C>G		5_prime_UTR	Exon 1 of 5	ENSP00000347433.4	Q8J025
	APCDD1	ENST00000423585.2	TSL:3	n.-19C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000404930.2	X6RH63
	APCDD1	ENST00000582723.1	TSL:3	n.-19C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000463110.1	J3KTR1

Frequencies

GnomAD3 genomes AF: 1.00 AC: 151875 AN: 151876 Hom.: 75937 Cov.: 32

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 131552 AN: 131552 AF XY: 1.00

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 1.00 AC: 1380049 AN: 1380052 Hom.: 690023 Cov.: 64 AF XY: 1.00 AC XY: 680822 AN XY: 680824

African (AFR) AF: 1.00 AC: 28802 AN: 28802

American (AMR) AF: 1.00 AC: 34463 AN: 34464

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 24440 AN: 24440

East Asian (EAS) AF: 1.00 AC: 33336 AN: 33336

South Asian (SAS) AF: 1.00 AC: 77005 AN: 77006

European-Finnish (FIN) AF: 1.00 AC: 47760 AN: 47760

Middle Eastern (MID) AF: 1.00 AC: 5050 AN: 5050

European-Non Finnish (NFE) AF: 1.00 AC: 1072051 AN: 1072052

Other (OTH) AF: 1.00 AC: 57142 AN: 57142

GnomAD4 genome AF: 1.00 AC: 151981 AN: 151982 Hom.: 75990 Cov.: 32 AF XY: 1.00 AC XY: 74272 AN XY: 74272

African (AFR) AF: 1.00 AC: 41535 AN: 41536

American (AMR) AF: 1.00 AC: 15284 AN: 15284

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3468 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5102 AN: 5102

South Asian (SAS) AF: 1.00 AC: 4832 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10530 AN: 10530

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 67910 AN: 67910

Other (OTH) AF: 1.00 AC: 2116 AN: 2116

Alfa AF: 1.00 Hom.: 12894

Bravo AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.6
DANN	Benign	0.53
PhyloP100		-2.6
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs28769876; hg19: chr18-10454960;