rs4647277

Positions:

• chr3-37017018-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000249.4(MLH1):​c.791-488A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 800,902 control chromosomes in the GnomAD database, including 79,834 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (16014 hom., cov: 32)
  • Exomes 𝑓: 0.43 (63820 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.32

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

RPL29P11 (HGNC:36905): (ribosomal protein L29 pseudogene 11)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.791-488A>G		intron_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.791-488A>G		intron_variant		1	NM_000249.4	ENSP00000231790	P1
RPL29P11	ENST00000494408.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68091 AN: 151884 Hom.: 16003 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.0772

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.429 AC: 278593 AN: 648900 Hom.: 63820 Cov.: 8 AF XY: 0.423 AC XY: 147570 AN XY: 348472

Gnomad4 AFR exome AF: 0.469

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.448 AC: 68132 AN: 152002 Hom.: 16014 Cov.: 32 AF XY: 0.439 AC XY: 32641 AN XY: 74294

Gnomad4 AFR AF: 0.467

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.0772

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.401

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.432

Alfa AF: 0.464 Hom.: 3900

Bravo AF: 0.451

Asia WGS AF: 0.210 AC: 734 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.57
DANN	Benign	0.49

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: rs4647277; hg19: chr3-37058509;