rs188830619

chr1-45331876-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001048174.2(MUTYH):c.914-27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,602,248 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: MUTYH NM_001048174.2 intron
• Scores: Splicing: ADA: 0.00002032
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.250

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-45331876-C-T is Benign according to our data. Variant chr1-45331876-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 371680.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr1-45331876-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001048174.2	c.914-27G>A		intron_variant		ENST00000456914.7
MUTYH	NM_001128425.2	c.998-27G>A		intron_variant		ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7	c.914-27G>A		intron_variant		1	NM_001048174.2	A1
MUTYH	ENST00000710952.2	c.998-27G>A		intron_variant			NM_001128425.2

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00121 AC: 276 AN: 228582 Hom.: 0 AF XY: 0.00124 AC XY: 154 AN XY: 124480

Gnomad AFR exome AF: 0.000291

Gnomad AMR exome AF: 0.000340

Gnomad ASJ exome AF: 0.000636

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000412

Gnomad FIN exome AF: 0.000256

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00183 AC: 2653 AN: 1449894 Hom.: 3 Cov.: 36 AF XY: 0.00178 AC XY: 1282 AN XY: 720242

Gnomad4 AFR exome AF: 0.000302

Gnomad4 AMR exome AF: 0.000326

Gnomad4 ASJ exome AF: 0.000505

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000247

Gnomad4 FIN exome AF: 0.000403

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74498

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000997

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Familial adenomatous polyposis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

May 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	16
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs188830619; hg19: chr1-45797548; COSMIC: COSV104641853; COSMIC: COSV104641853;