rs748512468

Variant names:

• chr1-45340203-C-A
• rs748512468
• NM_025077.4:c.-50C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-45340203-C-A
• chr1-45340203-C-G
• chr1-45340203-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_Moderate

The NM_001407071.1(MUTYH):c.-7G>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. Note: NM_001407071.1 is not a MANE Select or MANE Plus Clinical transcript for MUTYH; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,268 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MUTYH NM_001407071.1 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.02241
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

Genes affected

TOE1 (HGNC:15954): (target of EGR1, exonuclease) Enables poly(A)-specific ribonuclease activity and snRNA binding activity. Involved in snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Jul 2025]

TOE1 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 7

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

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: G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00473) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001407071.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOE1 NM_025077.4	MANE Select	c.-50C>A	5_prime_UTR	Exon 1 of 8	Prot: NP_079353.3
	MUTYH NM_001128425.2	MANE Plus Clinical	c.36+16G>T	intron	Intron 1 of 15	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001407071.1		c.-7G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	Prot: NP_001394000.1 UniProt:

TOE1 NM_025077.4

MANE Select

HGVSc / HGVSpc.-50C>A

Exon rankExon 1 of 8

5_prime_UTR

Prot: NP_079353.3

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.36+16G>T

Exon rankIntron 1 of 15

intron

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001407071.1

HGVSc / HGVSpc.-7G>T

Exon rankExon 1 of 16

5_prime_UTR_premature_start_codon_gain

Prot: NP_001394000.1UniProt: Q9UIF7-5E5KP28

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOE1 ENST00000372090.6	TSL:1MANE Select	c.-50C>A	5_prime_UTR	Exon 1 of 8	Prot: ENSP00000361162.5 UniProt:
	MUTYH ENST00000710952.2	MANE Plus Clinical	c.36+16G>T	intron	Intron 1 of 15	Prot: ENSP00000518552.2 UniProt:
	MUTYH ENST00000372098.7	TSL:1	c.36+16G>T	intron	Intron 1 of 15	Prot: ENSP00000361170.3 UniProt:

TOE1 ENST00000372090.6

TSL:1MANE Select

HGVSc / HGVSpc.-50C>A

Exon rankExon 1 of 8

5_prime_UTR

Prot: ENSP00000361162.5UniProt: Q96GM8-1

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.36+16G>T

Exon rankIntron 1 of 15

intron

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.36+16G>T

Exon rankIntron 1 of 15

intron

Prot: ENSP00000361170.3UniProt: Q9UIF7-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:248788	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461268	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial adenomatous polyposis 2 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.34
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.91
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
PhyloP100	Benign	1.3
PromoterAI	N/A	-0.11	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.022
dbscSNV1_RF	Benign	0.19
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs748512468;

hg19: chr1-45805875;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar