rs72541809

Variant names:

• chr5-112837553-G-A
• rs72541809
• NM_000038.6:c.1959G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112837553-G-A
• chr5-112837553-G-C
• chr5-112837553-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000038.6(APC):​c.1959G>A​(p.Arg653Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,610,582 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R653R) has been classified as Pathogenic. The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (27 hom.)
• Consequence: APC NM_000038.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.003458
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27 O:1
• Conservation: PhyloP100: 3.35
• Publications: 14 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

ENSG00000258864 (HGNC:):

ACMG classification

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 5-112837553-G-A is Benign according to our data. Variant chr5-112837553-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00548 (833/152138) while in subpopulation NFE AF = 0.00463 (315/68002). AF 95% confidence interval is 0.00421. There are 4 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. 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_000038.6	MANE Select	c.1959G>A	p.Arg653Arg	splice_region synonymous	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.2043G>A	p.Arg681Arg	splice_region synonymous	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.2013G>A	p.Arg671Arg	splice_region synonymous	Exon 17 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.1959G>A	p.Arg653Arg	splice_region synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.1959G>A	p.Arg653Arg	splice_region synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.*157G>A		splice_region non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152020 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0398

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00504 AC: 1261 AN: 250358 AF XY: 0.00509

Gnomad AFR exome AF: 0.000745

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0318

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00409 AC: 5972 AN: 1458444 Hom.: 27 Cov.: 31 AF XY: 0.00406 AC XY: 2947 AN XY: 725370

African (AFR) AF: 0.000748 AC: 25 AN: 33428

American (AMR) AF: 0.00128 AC: 57 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86096

European-Finnish (FIN) AF: 0.0292 AC: 1559 AN: 53312

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.00369 AC: 4090 AN: 1109134

Other (OTH) AF: 0.00340 AC: 205 AN: 60296

GnomAD4 genome AF: 0.00548 AC: 833 AN: 152138 Hom.: 4 Cov.: 32 AF XY: 0.00707 AC XY: 526 AN XY: 74370

African (AFR) AF: 0.000771 AC: 32 AN: 41494

American (AMR) AF: 0.00334 AC: 51 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0398 AC: 421 AN: 10572

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00463 AC: 315 AN: 68002

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00353 Hom.: 4

Bravo AF: 0.00245

EpiCase AF: 0.00469

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	7	not provided (7)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	Familial adenomatous polyposis 1 (4)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Familial multiple polyposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		3.4
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs72541809; hg19: chr5-112173250;