rs1312050427

Variant names:

• chr5-112707880-C-A
• rs1312050427
• NM_001407446.1:c.163C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112707880-C-A
• chr5-112707880-C-G
• chr5-112707880-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001407446.1(APC):​c.163C>A​(p.Gln55Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,216,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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. Q55R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: APC NM_001407446.1 missense, splice_region
• Scores: Splicing: ADA: 0.002944
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.58
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19544974).

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.163C>A	p.Gln55Lys	missense splice_region	Exon 1 of 16	NP_001394375.1
	APC	NM_001407447.1		c.-21C>A		splice_region	Exon 1 of 17	NP_001394376.1
	APC	NM_001354897.2		c.163C>A	p.Gln55Lys	missense splice_region	Exon 1 of 15	NP_001341826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000507379.6	TSL:2	c.163C>A	p.Gln55Lys	missense splice_region	Exon 1 of 14	ENSP00000423224.2
	APC	ENST00000951167.1		c.-19+231C>A		intron	N/A	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-19+231C>A		intron	N/A	ENSP00000426541.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000750 AC: 1 AN: 133360 AF XY: 0.0000138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000410

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: 0.0000140 AC: 17 AN: 1216266 Hom.: 0 Cov.: 31 AF XY: 0.00000673 AC XY: 4 AN XY: 594076

African (AFR) AF: 0.00 AC: 0 AN: 28218

American (AMR) AF: 0.0000978 AC: 3 AN: 30666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20944

East Asian (EAS) AF: 0.00 AC: 0 AN: 24192

South Asian (SAS) AF: 0.0000521 AC: 4 AN: 76792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4530

European-Non Finnish (NFE) AF: 0.00000722 AC: 7 AN: 969732

Other (OTH) AF: 0.0000623 AC: 3 AN: 48142

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Benign	0.92
Eigen	Benign	0.058
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.60	T
PhyloP100		2.6
PROVEAN	Benign	2.8	N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
MutPred		0.26		Gain of methylation at Q55 (P = 0.0099)
MVP		0.77
ClinPred		0.75	D
GERP RS		4.2
PromoterAI		0.26	Neutral
Mutation Taster		=199/101	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.032

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

Other links and lift over

dbSNP: rs1312050427; hg19: chr5-112043577;