rs730881737

Variant names:

• chr3-37025634-C-A
• rs730881737
• NM_000249.4:c.1039-3C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-37025634-C-A
• chr3-37025634-C-G
• chr3-37025634-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000249.4(MLH1):​c.1039-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Scores: Splicing: ADA: 0.9654
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-3C>A		splice_region_variant, intron_variant	Intron 11 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1039-3C>A		splice_region_variant, intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 25 AN: 103528 Hom.: 0 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.000298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000351

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00160

Gnomad SAS AF: 0.000906

Gnomad FIN AF: 0.000489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000895

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000196 AC: 3 AN: 152942 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 86352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000122

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000258

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00632 AC: 5119 AN: 809456 Hom.: 0 Cov.: 20 AF XY: 0.00589 AC XY: 2399 AN XY: 407168

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.00167

Gnomad4 ASJ exome AF: 0.00420

Gnomad4 EAS exome AF: 0.00461

Gnomad4 SAS exome AF: 0.00456

Gnomad4 FIN exome AF: 0.000763

Gnomad4 NFE exome AF: 0.00687

Gnomad4 OTH exome AF: 0.00625

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000241 AC: 25 AN: 103556 Hom.: 0 Cov.: 24 AF XY: 0.000167 AC XY: 8 AN XY: 47974

Gnomad4 AFR AF: 0.000298

Gnomad4 AMR AF: 0.000350

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00161

Gnomad4 SAS AF: 0.000909

Gnomad4 FIN AF: 0.000489

Gnomad4 NFE AF: 0.0000895

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 17, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1039-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 12 in the MLH1 gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881737; hg19: chr3-37067125;