5-112707765-T-G

Variant names:

• chr5-112707765-T-G
• rs980704771
• NM_001407446.1:c.48T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001407446.1(APC):​c.48T>G​(p.Ser16Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000985 in 1,218,364 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S16S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000098 (1 hom.)
• Consequence: APC NM_001407446.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.50
• Publications: 1 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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-112707765-T-G is Benign according to our data. Variant chr5-112707765-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469797.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_001407446.1		c.48T>G	p.Ser16Ser	synonymous	Exon 1 of 16	NP_001394375.1
	APC	NM_001354897.2		c.48T>G	p.Ser16Ser	synonymous	Exon 1 of 15	NP_001341826.1
	APC	NM_001127511.3		c.48T>G	p.Ser16Ser	synonymous	Exon 1 of 14	NP_001120983.2	P25054-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000507379.6	TSL:2	c.48T>G	p.Ser16Ser	synonymous	Exon 1 of 14	ENSP00000423224.2	P25054-3
	APC	ENST00000951167.1		c.-19+116T>G		intron	N/A	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-19+116T>G		intron	N/A	ENSP00000426541.2	P25054-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000985 AC: 12 AN: 1218364 Hom.: 1 Cov.: 31 AF XY: 0.0000118 AC XY: 7 AN XY: 595220

African (AFR) AF: 0.000353 AC: 10 AN: 28306

American (AMR) AF: 0.00 AC: 0 AN: 30762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21052

East Asian (EAS) AF: 0.00 AC: 0 AN: 24240

South Asian (SAS) AF: 0.00 AC: 0 AN: 76906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13126

Middle Eastern (MID) AF: 0.000204 AC: 1 AN: 4894

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 970784

Other (OTH) AF: 0.0000207 AC: 1 AN: 48294

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial adenomatous polyposis 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.2
DANN	Benign	0.67
PhyloP100		-1.5
PromoterAI		0.040	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: rs980704771; hg19: chr5-112043462;