rs185346146

Variant names:

• chr5-112707595-C-A
• rs185346146
• NM_001407446.1:c.-123C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112707595-C-A
• chr5-112707595-C-G
• chr5-112707595-C-T

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.-123C>A 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 0.00000106 in 944,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• 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 (BayesDel_noAF=-0.23).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.-123C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16		NP_001394375.1
APC	NM_001407447.1	c.-306C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17		NP_001394376.1
APC	NM_001407448.1	c.-73C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17		NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000509732.6	c.-73C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	4		ENSP00000426541.2
APC	ENST00000507379.6	c.-123C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	2		ENSP00000423224.2
APC	ENST00000505350.2	n.-123C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	3		ENSP00000481752.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000106 AC: 1 AN: 944620 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 463308

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

African (AFR) AF: 0.00 AC: 0 AN: 22684

American (AMR) AF: 0.00 AC: 0 AN: 26500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16970

East Asian (EAS) AF: 0.00 AC: 0 AN: 21912

South Asian (SAS) AF: 0.00 AC: 0 AN: 66578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 0.00000136 AC: 1 AN: 735946

Other (OTH) AF: 0.00 AC: 0 AN: 38526

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		1.5
PromoterAI		0.00090	Neutral

Splicing

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

Other links and lift over

dbSNP: rs185346146; hg19: chr5-112043292;