20-58461509-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153360.3(APCDD1L):c.787G>T(p.Asp263Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000231 in 1,297,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: APCDD1L NM_153360.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

Genes affected

APCDD1L (HGNC:26892): (APC down-regulated 1 like) Predicted to enable Wnt-protein binding activity. Predicted to be involved in negative regulation of Wnt signaling pathway. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APCDD1L	NM_153360.3	c.787G>T	p.Asp263Tyr	missense_variant	4/4	ENST00000371149.8
APCDD1L	NM_001304787.2	c.820G>T	p.Asp274Tyr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APCDD1L	ENST00000371149.8	c.787G>T	p.Asp263Tyr	missense_variant	4/4	1	NM_153360.3	P1
APCDD1L	ENST00000491015.1	n.198G>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000359 AC: 3 AN: 83512 Hom.: 0 AF XY: 0.0000238 AC XY: 1 AN XY: 41946

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000231 AC: 3 AN: 1297612 Hom.: 0 Cov.: 30 AF XY: 0.00000159 AC XY: 1 AN XY: 627962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.787G>T (p.D263Y) alteration is located in exon 4 (coding exon 4) of the APCDD1L gene. This alteration results from a G to T substitution at nucleotide position 787, causing the aspartic acid (D) at amino acid position 263 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.086
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.65
MVP		0.11
MPC		1.1
ClinPred		0.56	D
GERP RS		-0.013
Varity_R		0.32
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs894992227; hg19: chr20-57036565;