1-45334419-G-C

Position:

• chr1-45334419-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001048174.2(MUTYH):​c.87C>G​(p.Asn29Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N29S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56

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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08837026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.87C>G	p.Asn29Lys	missense_variant	2/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.87C>G	p.Asn29Lys	missense_variant	2/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.633C>G		non_coding_transcript_exon_variant	6/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251484 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.34
DEOGEN2	Benign	0.034	.;.;.;.;.;.;T;.;.;.;.;.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.87	.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.088	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.30	N;N;N;N;N;N;N;N;N;N;N;D;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.18	T;T;D;T;D;T;D;D;T;T;T;D;T;D;D
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;D;T;T;D
Polyphen		0.0, 0.0070	.;.;.;.;.;.;B;B;.;.;B;.;.;.;.
Vest4		0.26
MutPred		0.13		.;.;.;.;.;.;Loss of ubiquitination at K47 (P = 0.0183);Loss of ubiquitination at K47 (P = 0.0183);Loss of ubiquitination at K47 (P = 0.0183);.;Loss of ubiquitination at K47 (P = 0.0183);.;.;.;.;
MVP		0.45
MPC		0.13
ClinPred		0.60	D
GERP RS		1.4
Varity_R		0.043
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs141679570; hg19: chr1-45800091;