rs7156586

Positions:

• chr14-75039527-A-T

Variant summary

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

The NM_001040108.2(MLH3):​c.3570+384T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 151,796 control chromosomes in the GnomAD database, including 10,328 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 0.33 (10328 hom., cov: 29)
• Consequence: MLH3 NM_001040108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250

Genes affected

MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.3570+384T>A		intron_variant		ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.3570+384T>A		intron_variant		5	NM_001040108.2	ENSP00000348020	P1

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50555 AN: 151676 Hom.: 10326 Cov.: 29

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.367

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.333 AC: 50559 AN: 151796 Hom.: 10328 Cov.: 29 AF XY: 0.334 AC XY: 24807 AN XY: 74172

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.640

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.363

Alfa AF: 0.379 Hom.: 1672

Bravo AF: 0.328

Asia WGS AF: 0.400 AC: 1393 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.2
DANN	Benign	0.63

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: rs7156586; hg19: chr14-75506230;