rs74318065

Variant names:

• chr1-45331227-C-G
• rs74318065
• NM_001128425.2:c.1431G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-45331227-C-G
• chr1-45331227-C-T
• chr1-45331227-C-A

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_001048174.2(MUTYH):​c.1347G>C​(p.Thr449Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,614,218 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T449T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (61 hom.)
• Consequence: MUTYH NM_001048174.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:23
• Conservation: PhyloP100: 0.762
• Publications: 22 publications found

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (REVEL=0.039).
• BP6: Variant 1-45331227-C-G is Benign according to our data. Variant chr1-45331227-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 183787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.762 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00528 (804/152328) while in subpopulation EAS AF = 0.0314 (163/5192). AF 95% confidence interval is 0.0275. There are 12 homozygotes in GnomAd4. There are 445 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048174.2. 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
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.1431G>C	p.Thr477Thr	synonymous	Exon 14 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.1347G>C	p.Thr449Thr	synonymous	Exon 14 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1422G>C	p.Thr474Thr	synonymous	Exon 14 of 16	NP_036354.1	Q9UIF7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1431G>C	p.Thr477Thr	synonymous	Exon 14 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1347G>C	p.Thr449Thr	synonymous	Exon 14 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1422G>C	p.Thr474Thr	synonymous	Exon 14 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 801 AN: 152210 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00987

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00461 AC: 1159 AN: 251482 AF XY: 0.00433

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0249

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00264 AC: 3853 AN: 1461890 Hom.: 61 Cov.: 32 AF XY: 0.00266 AC XY: 1935 AN XY: 727244

African (AFR) AF: 0.00959 AC: 321 AN: 33480

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00451 AC: 118 AN: 26136

East Asian (EAS) AF: 0.0398 AC: 1579 AN: 39700

South Asian (SAS) AF: 0.00358 AC: 309 AN: 86258

European-Finnish (FIN) AF: 0.00839 AC: 448 AN: 53416

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000682 AC: 758 AN: 1112012

Other (OTH) AF: 0.00358 AC: 216 AN: 60396

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152328 Hom.: 12 Cov.: 33 AF XY: 0.00597 AC XY: 445 AN XY: 74496

African (AFR) AF: 0.00977 AC: 406 AN: 41562

American (AMR) AF: 0.00216 AC: 33 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.0314 AC: 163 AN: 5192

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4832

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000999 AC: 68 AN: 68034

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00560

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	7	not specified (7)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Familial adenomatous polyposis 2 (3)
-	1	-	Carcinoma of colon (1)
-	-	1	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.40
DANN	Benign	0.62
PhyloP100		0.76
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs74318065; hg19: chr1-45796899; COSMIC: COSV58344222; COSMIC: COSV58344222;