NM_001407447.1:c.-51C>T

Variant names:

• chr5-112707850-C-T
• rs755954869
• NM_001407447.1:c.-51C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001407447.1(APC):​c.-51C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,370,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: APC NM_001407447.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.391
• Publications: 3 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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13876659).
• BP6: Variant 5-112707850-C-T is Benign according to our data. Variant chr5-112707850-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469789.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407447.1. 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
	APC	NM_001407447.1		c.-51C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001394376.1	R4GMU6
	APC	NM_001354895.2		c.-51C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001341824.1	P25054-1
	APC	NM_001407452.1		c.-51C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001394381.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000507379.6	TSL:2	c.133C>T	p.Arg45Cys	missense	Exon 1 of 14	ENSP00000423224.2	P25054-3
	APC	ENST00000951167.1		c.-19+201C>T		intron	N/A	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-19+201C>T		intron	N/A	ENSP00000426541.2	P25054-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000372 AC: 5 AN: 134330 AF XY: 0.0000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.0000759

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 13 AN: 1218086 Hom.: 0 Cov.: 31 AF XY: 0.00000336 AC XY: 2 AN XY: 595056

African (AFR) AF: 0.00 AC: 0 AN: 28296

American (AMR) AF: 0.00 AC: 0 AN: 30744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21034

East Asian (EAS) AF: 0.00 AC: 0 AN: 24242

South Asian (SAS) AF: 0.00 AC: 0 AN: 76876

European-Finnish (FIN) AF: 0.0000763 AC: 1 AN: 13106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4832

European-Non Finnish (NFE) AF: 0.0000103 AC: 10 AN: 970672

Other (OTH) AF: 0.0000414 AC: 2 AN: 48284

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000566 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Familial adenomatous polyposis 1 (2)
-	1	-	APC-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0035	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	13
DANN	Uncertain	1.0
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.25	T
PhyloP100		0.39
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.031	D
MVP		0.79
ClinPred		0.41	T
GERP RS		2.1
PromoterAI		-0.0043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs755954869; hg19: chr5-112043547;