5-112707865-T-G

Variant names:

• chr5-112707865-T-G
• rs1488176769
• NM_001407446.1:c.148T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001407446.1(APC):​c.148T>G​(p.Trp50Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,217,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W50C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: APC NM_001407446.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.321
• Publications: 0 publications found

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07850462).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407446.1. 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
	APC	NM_001407446.1		c.148T>G	p.Trp50Gly	missense	Exon 1 of 16	NP_001394375.1
	APC	NM_001354897.2		c.148T>G	p.Trp50Gly	missense	Exon 1 of 15	NP_001341826.1
	APC	NM_001127511.3		c.148T>G	p.Trp50Gly	missense	Exon 1 of 14	NP_001120983.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000507379.6	TSL:2	c.148T>G	p.Trp50Gly	missense	Exon 1 of 14	ENSP00000423224.2
	APC	ENST00000505350.2	TSL:3	n.148T>G		non_coding_transcript_exon	Exon 1 of 16	ENSP00000481752.1
	APC	ENST00000713636.1		n.-36T>G		non_coding_transcript_exon	Exon 1 of 17	ENSP00000518937.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.22e-7 AC: 1 AN: 1217160 Hom.: 0 Cov.: 31 AF XY: 0.00000168 AC XY: 1 AN XY: 594540

African (AFR) AF: 0.00 AC: 0 AN: 28256

American (AMR) AF: 0.00 AC: 0 AN: 30720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21000

East Asian (EAS) AF: 0.00 AC: 0 AN: 24200

South Asian (SAS) AF: 0.00 AC: 0 AN: 76842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 970204

Other (OTH) AF: 0.00 AC: 0 AN: 48216

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Sep 16, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with APC-related conditions. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of this non-coding change is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.026
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	14
DANN	Benign	0.64
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.59	T
PhyloP100		-0.32
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	0.29	T
MutPred		0.56		Gain of disorder (P = 0.003)
MVP		0.73
ClinPred		0.077	T
GERP RS		-1.5
PromoterAI		-0.00030	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1488176769; hg19: chr5-112043562;