14-75014613-T-C

Variant names:

• chr14-75014613-T-C
• rs764557856
• NM_001040108.2:c.*2469A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001040108.2(MLH3):​c.*2469A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 204,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.845
• Publications: 0 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
• intestinal polyposis syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000446 (68/152332) while in subpopulation NFE AF = 0.00075 (51/68022). AF 95% confidence interval is 0.000586. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.*2469A>G		3_prime_UTR	Exon 13 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.*2469A>G		3_prime_UTR	Exon 12 of 12	NP_055196.2	Q9UHC1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.*2469A>G		3_prime_UTR	Exon 13 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.*2469A>G		3_prime_UTR	Exon 12 of 12	ENSP00000370355.3	Q9UHC1-2

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000463 AC: 24 AN: 51796 Hom.: 0 Cov.: 0 AF XY: 0.000542 AC XY: 13 AN XY: 23994

African (AFR) AF: 0.000434 AC: 1 AN: 2304

American (AMR) AF: 0.00 AC: 0 AN: 1448

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 2 AN: 3264

East Asian (EAS) AF: 0.00 AC: 0 AN: 8202

South Asian (SAS) AF: 0.00 AC: 0 AN: 412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 326

European-Non Finnish (NFE) AF: 0.000540 AC: 17 AN: 31460

Other (OTH) AF: 0.000923 AC: 4 AN: 4336

GnomAD4 genome AF: 0.000446 AC: 68 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74498

African (AFR) AF: 0.0000721 AC: 3 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000336

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, hereditary nonpolyposis, type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.64
DANN	Benign	0.30
PhyloP100		-0.84

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: rs764557856; hg19: chr14-75481316;