3-37017018-A-G

Variant names:

• chr3-37017018-A-G
• rs4647277
• NM_000249.4:c.791-488A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. 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
	MLH1	NM_000249.4	MANE Select	c.791-488A>G		intron	N/A	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.791-488A>G		intron	N/A	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.692-488A>G		intron	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.791-488A>G		intron	N/A	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.791-488A>G		intron	N/A	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.791-488A>G		intron	N/A	ENSP00000416476.2	H0Y806

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

African (AFR) AF: 0.469 AC: 8150 AN: 17364

American (AMR) AF: 0.393 AC: 13804 AN: 35146

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 7949 AN: 18094

East Asian (EAS) AF: 0.118 AC: 4270 AN: 36172

South Asian (SAS) AF: 0.268 AC: 16529 AN: 61764

European-Finnish (FIN) AF: 0.408 AC: 14569 AN: 35724

Middle Eastern (MID) AF: 0.397 AC: 984 AN: 2478

European-Non Finnish (NFE) AF: 0.485 AC: 197933 AN: 408494

Other (OTH) AF: 0.428 AC: 14405 AN: 33664

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

African (AFR) AF: 0.467 AC: 19356 AN: 41436

American (AMR) AF: 0.445 AC: 6801 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1492 AN: 3466

East Asian (EAS) AF: 0.0772 AC: 399 AN: 5170

South Asian (SAS) AF: 0.247 AC: 1191 AN: 4820

European-Finnish (FIN) AF: 0.401 AC: 4226 AN: 10534

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33123 AN: 67982

Other (OTH) AF: 0.432 AC: 912 AN: 2110

Alfa AF: 0.464 Hom.: 3988

Bravo AF: 0.451

Asia WGS AF: 0.210 AC: 734 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.57
DANN	Benign	0.49
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4647277; hg19: chr3-37058509;