14-75039527-A-T

Variant names:

• chr14-75039527-A-T
• rs7156586
• NM_001040108.2:c.3570+384T>A

Variant summary

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

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]

MLH3 Gene-Disease associations (from GenCC):

• colorectal cancer, hereditary nonpolyposis, type 7

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.3570+384T>A		intron	N/A	NP_001035197.1
	MLH3	NM_014381.3		c.3570+384T>A		intron	N/A	NP_055196.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.3570+384T>A		intron	N/A	ENSP00000348020.2
	MLH3	ENST00000380968.6	TSL:1	c.3570+384T>A		intron	N/A	ENSP00000370355.3
	MLH3	ENST00000556257.5	TSL:5	c.3280+6849T>A		intron	N/A	ENSP00000451540.1

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

African (AFR) AF: 0.0882 AC: 3656 AN: 41434

American (AMR) AF: 0.415 AC: 6330 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1470 AN: 3466

East Asian (EAS) AF: 0.640 AC: 3286 AN: 5136

South Asian (SAS) AF: 0.321 AC: 1542 AN: 4806

European-Finnish (FIN) AF: 0.416 AC: 4377 AN: 10520

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28644 AN: 67896

Other (OTH) AF: 0.363 AC: 764 AN: 2104

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.2
DANN	Benign	0.63
PhyloP100		0.25
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: rs7156586; hg19: chr14-75506230;