chr1-45334484-C-T

Variant names:

• chr1-45334484-C-T
• rs3219484
• NM_001128425.2:c.64G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001407075.1(MUTYH):​c.-135G>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 0.0635 in 1,614,066 control chromosomes in the GnomAD database, including 3,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (244 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3499 hom.)
• Consequence: MUTYH NM_001407075.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24 O:1
• Conservation: PhyloP100: -0.185
• Publications: 79 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018110275).
• BP6: Variant 1-45334484-C-T is Benign according to our data. Variant chr1-45334484-C-T is described in ClinVar as Benign. ClinVar VariationId is 41760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407075.1. 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.64G>A	p.Val22Met	missense	Exon 2 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.22G>A	p.Val8Met	missense	Exon 2 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_001407075.1		c.-135G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001394004.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.64G>A	p.Val22Met	missense	Exon 2 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.22G>A	p.Val8Met	missense	Exon 2 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.64G>A	p.Val22Met	missense	Exon 2 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7118 AN: 152136 Hom.: 244 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0733

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0485 AC: 12191 AN: 251474 AF XY: 0.0496

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0748

Gnomad NFE exome AF: 0.0709

Gnomad OTH exome AF: 0.0485

GnomAD4 exome AF: 0.0653 AC: 95456 AN: 1461812 Hom.: 3499 Cov.: 32 AF XY: 0.0646 AC XY: 46945 AN XY: 727202

African (AFR) AF: 0.00986 AC: 330 AN: 33478

American (AMR) AF: 0.0193 AC: 864 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0428 AC: 1119 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0336 AC: 2896 AN: 86258

European-Finnish (FIN) AF: 0.0748 AC: 3996 AN: 53412

Middle Eastern (MID) AF: 0.0192 AC: 111 AN: 5768

European-Non Finnish (NFE) AF: 0.0742 AC: 82545 AN: 1111954

Other (OTH) AF: 0.0595 AC: 3594 AN: 60386

GnomAD4 genome AF: 0.0467 AC: 7117 AN: 152254 Hom.: 244 Cov.: 32 AF XY: 0.0460 AC XY: 3425 AN XY: 74456

African (AFR) AF: 0.0108 AC: 447 AN: 41542

American (AMR) AF: 0.0305 AC: 466 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4822

European-Finnish (FIN) AF: 0.0750 AC: 795 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0733 AC: 4987 AN: 68012

Other (OTH) AF: 0.0383 AC: 81 AN: 2114

Alfa AF: 0.0613 Hom.: 1649

Bravo AF: 0.0422

TwinsUK AF: 0.0725 AC: 269

ALSPAC AF: 0.0799 AC: 308

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.0694 AC: 597

ExAC AF: 0.0491 AC: 5967

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.0652

EpiControl AF: 0.0639

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	5	Familial adenomatous polyposis 2 (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	1	Breast carcinoma (1)
-	-	1	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.6
DANN	Benign	0.97
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.18
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.073
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.18	B
Vest4		0.17
MPC		0.12
ClinPred		0.0056	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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: rs3219484; hg19: chr1-45800156; COSMIC: COSV62742654;