rs554351451

Variant names:

• chr5-112707514-A-G
• rs554351451
• NM_001407446.1:c.-204A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001407446.1(APC):​c.-204A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 461,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.17

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]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 5-112707514-A-G is Benign according to our data. Variant chr5-112707514-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469859.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000716 (109/152196) while in subpopulation AMR AF = 0.0068 (104/15290). AF 95% confidence interval is 0.00574. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.-204A>G		5_prime_UTR_variant	Exon 1 of 16		NP_001394375.1
APC	NM_001407447.1	c.-387A>G		5_prime_UTR_variant	Exon 1 of 17		NP_001394376.1
APC	NM_001407448.1	c.-154A>G		5_prime_UTR_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.-154A>G		upstream_gene_variant		4		ENSP00000426541.2
APC	ENST00000507379.6	c.-204A>G		upstream_gene_variant		2		ENSP00000423224.2
APC	ENST00000505350.2	n.-204A>G		upstream_gene_variant		3		ENSP00000481752.1

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 152078 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000204 AC: 63 AN: 309506 Hom.: 1 Cov.: 4 AF XY: 0.000198 AC XY: 32 AN XY: 161262

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 9530

Gnomad4 AMR exome AF: 0.00394 AC: 57 AN: 14458

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 9750

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 19638

Gnomad4 SAS exome AF: 0.0000221 AC: 1 AN: 45296

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 8944

Gnomad4 NFE exome AF: 0.0000273 AC: 5 AN: 183230

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 17304

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152196 Hom.: 1 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74402

Gnomad4 AFR AF: 0.0000482 AC: 0.0000481603 AN: 0.0000481603

Gnomad4 AMR AF: 0.00680 AC: 0.00680183 AN: 0.00680183

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000193349 AN: 0.000193349

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.00002941 AN: 0.00002941

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000552

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

APC-related disorder Benign:1

Mar 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs554351451; hg19: chr5-112043211;