Genetic Variant NM_000249.4:c.1039-11_1039-8delTTTT (chr3-37025608-ATTTT-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.1039-11_1039-8delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 306,496 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:1

Conservation

PhyloP100: 0.431

Variant links:

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]

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 3-37025608-ATTTT-A is Benign according to our data. Variant chr3-37025608-ATTTT-A is described in ClinVar as [Benign]. Clinvar id is 1697941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00118 (305/258220) while in subpopulation AFR AF= 0.0066 (22/3334). AF 95% confidence interval is 0.00447. There are 3 homozygotes in gnomad4_exome. There are 141 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1039-11_1039-8delTTTT		splice_region_variant, intron_variant	Intron 11 of 18	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.1039-28_1039-25delTTTT		intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

48288

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000416

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000763

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00229

AC:

AN:

13956

Hom.:

AF XY:

0.00226

AC XY:

AN XY:

8400

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00232

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00433

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.00645

GnomAD4 exome

AF:

0.00118

AC:

305

AN:

258220

Hom.:

AF XY:

0.00110

AC XY:

141

AN XY:

128194

show subpopulations

Gnomad4 AFR exome

AF:

0.00660

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.000963

Gnomad4 EAS exome

AF:

0.00131

Gnomad4 SAS exome

AF:

0.00265

Gnomad4 FIN exome

AF:

0.000822

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.000145

AC:

AN:

48276

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

AN XY:

21494

show subpopulations

Gnomad4 AFR

AF:

0.000415

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000764

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

La Branchor

0.24

BranchPoint Hunter

2.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over