rs372105770

Variant names:

• chr18-10468580-A-G
• rs372105770
• NM_153000.5:c.170A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-10468580-A-G
• chr18-10468580-A-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_153000.5(APCDD1):​c.170A>G​(p.Lys57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K57I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: APCDD1 NM_153000.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15963224).
• BS2: High AC in GnomAdExome4 at 6 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.170A>G	p.Lys57Arg	missense	Exon 2 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.170A>G	p.Lys57Arg	missense	Exon 2 of 5	ENSP00000347433.4	Q8J025
	APCDD1	ENST00000578882.1	TSL:3	c.170A>G	p.Lys57Arg	missense	Exon 2 of 5	ENSP00000463104.1	J3KTQ6
	APCDD1	ENST00000423585.2	TSL:3	n.58+13541A>G		intron	N/A	ENSP00000404930.2	X6RH63

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251496 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000410 AC: 6 AN: 1461830 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.0000965 AC: 4 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.050
Sift	Benign	0.43	T
Sift4G	Benign	0.72	T
Polyphen		0.0030	B
Vest4		0.23
MVP		0.27
MPC		0.29
ClinPred		0.060	T
GERP RS		4.1
Varity_R		0.089
gMVP		0.38
Mutation Taster		=82/18	polymorphism

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: rs372105770; hg19: chr18-10468577;