NM_153000.5:c.243-6G>A

Variant names:

• chr18-10471524-G-A
• rs78536172
• NM_153000.5:c.243-6G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_153000.5(APCDD1):​c.243-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,613,964 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (25 hom.)
• Consequence: APCDD1 NM_153000.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003922
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.852
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-10471524-G-A is Benign according to our data. Variant chr18-10471524-G-A is described in ClinVar as Benign. ClinVar VariationId is 786435.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 277 AD gene.

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.243-6G>A		splice_region intron	N/A	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.243-6G>A		splice_region intron	N/A	ENSP00000347433.4	Q8J025
	APCDD1	ENST00000578882.1	TSL:3	c.243-6G>A		splice_region intron	N/A	ENSP00000463104.1	J3KTQ6
	APCDD1	ENST00000423585.2	TSL:3	n.59-13938G>A		intron	N/A	ENSP00000404930.2	X6RH63

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 151982 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.00997

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00410 AC: 1031 AN: 251248 AF XY: 0.00422

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.0171

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00234 AC: 3415 AN: 1461864 Hom.: 25 Cov.: 31 AF XY: 0.00254 AC XY: 1844 AN XY: 727232

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00217 AC: 97 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 262 AN: 26136

East Asian (EAS) AF: 0.0154 AC: 613 AN: 39700

South Asian (SAS) AF: 0.0112 AC: 966 AN: 86256

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53398

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.00108 AC: 1206 AN: 1112010

Other (OTH) AF: 0.00386 AC: 233 AN: 60392

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152100 Hom.: 6 Cov.: 33 AF XY: 0.00198 AC XY: 147 AN XY: 74372

African (AFR) AF: 0.000193 AC: 8 AN: 41456

American (AMR) AF: 0.00190 AC: 29 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3468

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5176

South Asian (SAS) AF: 0.00956 AC: 46 AN: 4812

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68002

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00165

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00219

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.44
PhyloP100		0.85
PromoterAI		-0.0076	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.11
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: rs78536172; hg19: chr18-10471521;