rs3219496

Variant names:

• chr1-45329371-G-T
• rs3219496
• NM_001128425.2:c.1585C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-45329371-G-T
• chr1-45329371-G-A
• chr1-45329371-G-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001048174.2(MUTYH):​c.1501C>A​(p.Leu501Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000808 in 1,614,220 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L501R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (18 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 1.64
• Publications: 13 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073990226).
• BP6: Variant 1-45329371-G-T is Benign according to our data. Variant chr1-45329371-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00154 (234/152332) while in subpopulation AMR AF = 0.0136 (208/15310). AF 95% confidence interval is 0.0121. There are 2 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1585C>A	p.Leu529Met	missense	Exon 16 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.1501C>A	p.Leu501Met	missense	Exon 16 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1576C>A	p.Leu526Met	missense	Exon 16 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.1585C>A	p.Leu529Met	missense	Exon 16 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1501C>A	p.Leu501Met	missense	Exon 16 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1576C>A	p.Leu526Met	missense	Exon 16 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152214 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00346 AC: 870 AN: 251490 AF XY: 0.00252

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000732 AC: 1070 AN: 1461888 Hom.: 18 Cov.: 31 AF XY: 0.000608 AC XY: 442 AN XY: 727246

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.0223 AC: 996 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112008

Other (OTH) AF: 0.000695 AC: 42 AN: 60396

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152332 Hom.: 2 Cov.: 31 AF XY: 0.00181 AC XY: 135 AN XY: 74492

African (AFR) AF: 0.000409 AC: 17 AN: 41574

American (AMR) AF: 0.0136 AC: 208 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000648 Hom.: 2

Bravo AF: 0.00284

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	Familial adenomatous polyposis 2 (4)
-	-	4	not provided (4)
-	-	2	Carcinoma of colon (2)
-	-	2	not specified (3)
-	-	1	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.24
Sift	Benign	0.059	T
Sift4G	Benign	0.13	T
Polyphen		0.89	P
Vest4		0.47
MVP		0.81
MPC		0.37
ClinPred		0.021	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.40
Mutation Taster		=90/10	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: rs3219496; hg19: chr1-45795043;