rs758579958

Variant names:

• chr1-45331868-G-A
• rs758579958
• NM_001128425.2:c.998-19C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001048174.2(MUTYH):​c.914-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,600,130 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MUTYH NM_001048174.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.360
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-45331868-G-A is Benign according to our data. Variant chr1-45331868-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 492066.

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.998-19C>T		intron	N/A	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.914-19C>T		intron	N/A	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.989-19C>T		intron	N/A	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.998-19C>T		intron	N/A	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.914-19C>T		intron	N/A	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.989-19C>T		intron	N/A	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000222 AC: 5 AN: 225062 AF XY: 0.0000245

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1447896 Hom.: 0 Cov.: 36 AF XY: 0.0000125 AC XY: 9 AN XY: 719088

African (AFR) AF: 0.0000302 AC: 1 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 42588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25670

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84976

European-Finnish (FIN) AF: 0.0000386 AC: 2 AN: 51854

Middle Eastern (MID) AF: 0.000563 AC: 3 AN: 5324

European-Non Finnish (NFE) AF: 0.00000995 AC: 11 AN: 1105336

Other (OTH) AF: 0.00 AC: 0 AN: 59786

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	Familial adenomatous polyposis 2 (1)
-	-	1	MUTYH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.084
DANN	Benign	0.47
PhyloP100		-0.36
PromoterAI		0.0014	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs758579958; hg19: chr1-45797540; COSMIC: COSV58343423; COSMIC: COSV58343423;