3-37025608-ATTTTTTTTT-ATTTTTT

Position:

• chr3-37025608-ATTTTTTTTT-ATTTTTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000249.4(MLH1):​c.1039-10_1039-8del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 306,194 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0028 (4 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.431

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 3-37025608-ATTT-A is Benign according to our data. Variant chr3-37025608-ATTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1697940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00285 (734/257920) while in subpopulation AFR AF= 0.00987 (33/3342). AF 95% confidence interval is 0.00723. There are 4 homozygotes in gnomad4_exome. There are 346 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-10_1039-8del		intron_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1039-10_1039-8del		intron_variant		1	NM_000249.4	ENSP00000231790	P1

Frequencies

GnomAD3 genomes AF: 0.000104 AC: 5 AN: 48286 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000333

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: 0.0000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00559 AC: 78 AN: 13956 Hom.: 0 AF XY: 0.00369 AC XY: 31 AN XY: 8400

Gnomad AFR exome AF: 0.0597

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.0222

Gnomad SAS exome AF: 0.00325

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.00629

Gnomad OTH exome AF: 0.00323

GnomAD4 exome AF: 0.00285 AC: 734 AN: 257920 Hom.: 4 AF XY: 0.00270 AC XY: 346 AN XY: 128056

Gnomad4 AFR exome AF: 0.00987

Gnomad4 AMR exome AF: 0.00395

Gnomad4 ASJ exome AF: 0.00385

Gnomad4 EAS exome AF: 0.00363

Gnomad4 SAS exome AF: 0.00436

Gnomad4 FIN exome AF: 0.00413

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.00413

GnomAD4 genome AF: 0.000104 AC: 5 AN: 48274 Hom.: 0 Cov.: 0 AF XY: 0.0000930 AC XY: 2 AN XY: 21494

Gnomad4 AFR AF: 0.000332

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: 0.0000382

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

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

Other links and lift over

dbSNP: rs57509953; hg19: chr3-37067099;