1-45339894-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001048174.2(MUTYH):c.-7+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 1,401,720 control chromosomes in the GnomAD database, including 683,553 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 Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74671 hom., cov: 31)

Exomes 𝑓: 0.99 ( 608882 hom. )

Consequence

MUTYH
NM_001048174.2 splice_region, intron

Scores

Splicing: ADA: 0.00004900

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.00

Publications

16 publications found

Variant links:

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 links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

TOE1 (HGNC:15954): (target of EGR1, exonuclease) Enables poly(A)-specific ribonuclease activity and snRNA binding activity. Involved in RNA phosphodiester bond hydrolysis, exonucleolytic and snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Apr 2022]

TOE1 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 7
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

TOE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-45339894-G-C is Benign according to our data. Variant chr1-45339894-G-C is described in ClinVar as Benign. ClinVar VariationId is 1244445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MUTYH	NM_001128425.2	MANE Plus Clinical	c.36+325C>G	intron	N/A	NP_001121897.1
MUTYH	NM_001048174.2	MANE Select	c.-7+5C>G	splice_region intron	N/A	NP_001041639.1
MUTYH	NM_001407089.1		c.-239C>G	5_prime_UTR	Exon 1 of 16	NP_001394018.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MUTYH	ENST00000710952.2	MANE Plus Clinical	c.36+325C>G	intron	N/A	ENSP00000518552.2
MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.-7+5C>G	splice_region intron	N/A	ENSP00000407590.2
MUTYH	ENST00000372098.7	TSL:1	c.36+325C>G	intron	N/A	ENSP00000361170.3

Frequencies

GnomAD3 genomes

AF:

0.990

AC:

150678

AN:

152156

Hom.:

74611

Cov.:

show subpopulations

Gnomad AFR

AF:

0.997

Gnomad AMI

AF:

0.987

Gnomad AMR

AF:

0.988

Gnomad ASJ

AF:

0.994

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.997

Gnomad FIN

AF:

0.994

Gnomad MID

AF:

0.991

Gnomad NFE

AF:

0.985

Gnomad OTH

AF:

0.989

GnomAD2 exomes

AF:

0.990

AC:

168681

AN:

170428

AF XY:

0.990

show subpopulations

Gnomad AFR exome

AF:

0.997

Gnomad AMR exome

AF:

0.991

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.991

Gnomad NFE exome

AF:

0.984

Gnomad OTH exome

AF:

0.986

GnomAD4 exome

AF:

0.987

AC:

1233495

AN:

1249446

Hom.:

608882

Cov.:

AF XY:

0.987

AC XY:

606722

AN XY:

614462

show subpopulations

African (AFR)

AF:

0.998

AC:

27702

AN:

27766

American (AMR)

AF:

0.991

AC:

32029

AN:

32324

Ashkenazi Jewish (ASJ)

AF:

0.995

AC:

19985

AN:

20080

East Asian (EAS)

AF:

1.00

AC:

22308

AN:

22310

South Asian (SAS)

AF:

0.996

AC:

77580

AN:

77868

European-Finnish (FIN)

AF:

0.991

AC:

31923

AN:

32208

Middle Eastern (MID)

AF:

0.998

AC:

4856

AN:

4866

European-Non Finnish (NFE)

AF:

0.985

AC:

969156

AN:

983558

Other (OTH)

AF:

0.989

AC:

47956

AN:

48466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

968

1935

2903

3870

4838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21086

42172

63258

84344

105430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.990

AC:

150797

AN:

152274

Hom.:

74671

Cov.:

AF XY:

0.991

AC XY:

73822

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.997

AC:

41415

AN:

41558

American (AMR)

AF:

0.988

AC:

15113

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.994

AC:

3452

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5160

AN:

5162

South Asian (SAS)

AF:

0.997

AC:

4812

AN:

4826

European-Finnish (FIN)

AF:

0.994

AC:

10548

AN:

10614

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

0.985

AC:

67017

AN:

68022

Other (OTH)

AF:

0.989

AC:

2088

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

150

225

300

375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.985

Hom.:

7779

Bravo

AF:

0.990

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.25

(source)

DANN

Benign

0.50

PhyloP100

-2.0

PromoterAI

0.031

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over