Genetic Variant NM_001128425.2:c.36+325C>T (chr1-45339894-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001128425.2(MUTYH):c.36+325C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 152,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

MUTYH
NM_001128425.2 intron

Scores

Splicing: ADA: 0.00004522

Clinical Significance

Not reported in ClinVar

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, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

TOE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. 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>T	intron	N/A	NP_001121897.1
MUTYH	NM_001048174.2	MANE Select	c.-7+5C>T	splice_region intron	N/A	NP_001041639.1
MUTYH	NM_001407089.1		c.-239C>T	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>T	intron	N/A	ENSP00000518552.2
MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.-7+5C>T	splice_region intron	N/A	ENSP00000407590.2
MUTYH	ENST00000372098.7	TSL:1	c.36+325C>T	intron	N/A	ENSP00000361170.3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000399

AC:

AN:

170428

AF XY:

0.000291

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000375

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00345

Gnomad NFE exome

AF:

0.0000864

Gnomad OTH exome

AF:

0.000421

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000183

AC:

229

AN:

1249500

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

111

AN XY:

614496

show subpopulations

African (AFR)

AF:

0.0000360

AC:

AN:

27766

American (AMR)

AF:

0.0000309

AC:

AN:

32330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20080

East Asian (EAS)

AF:

0.00

AC:

AN:

22310

South Asian (SAS)

AF:

0.00

AC:

AN:

77868

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

32212

Middle Eastern (MID)

AF:

0.000206

AC:

AN:

4866

European-Non Finnish (NFE)

AF:

0.000128

AC:

126

AN:

983602

Other (OTH)

AF:

0.000186

AC:

AN:

48466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000171

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41560

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000624

Hom.:

7779

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.42

(source)

DANN

Benign

0.95

PhyloP100

-2.0

PromoterAI

0.0091

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000045

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.010

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