14-75046439-C-T

Variant names:

• chr14-75046439-C-T
• rs28756993
• NM_001040108.2:c.3217G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040108.2(MLH3):​c.3217G>A​(p.Asp1073Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,614,186 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D1073D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (8 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.50
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041101575).
• BP6: Variant 14-75046439-C-T is Benign according to our data. Variant chr14-75046439-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00519 (790/152306) while in subpopulation AFR AF = 0.0167 (695/41568). AF 95% confidence interval is 0.0157. There are 4 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.3217G>A	p.Asp1073Asn	missense	Exon 2 of 13	NP_001035197.1
	MLH3	NM_014381.3		c.3217G>A	p.Asp1073Asn	missense	Exon 2 of 12	NP_055196.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.3217G>A	p.Asp1073Asn	missense	Exon 2 of 13	ENSP00000348020.2
	MLH3	ENST00000380968.6	TSL:1	c.3217G>A	p.Asp1073Asn	missense	Exon 2 of 12	ENSP00000370355.3
	MLH3	ENST00000556257.5	TSL:5	c.3217G>A	p.Asp1073Asn	missense	Exon 2 of 7	ENSP00000451540.1

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 787 AN: 152188 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00157 AC: 395 AN: 251456 AF XY: 0.00120

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000685 AC: 1001 AN: 1461880 Hom.: 8 Cov.: 34 AF XY: 0.000616 AC XY: 448 AN XY: 727240

African (AFR) AF: 0.0187 AC: 627 AN: 33480

American (AMR) AF: 0.00266 AC: 119 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1112002

Other (OTH) AF: 0.00141 AC: 85 AN: 60396

GnomAD4 genome AF: 0.00519 AC: 790 AN: 152306 Hom.: 4 Cov.: 32 AF XY: 0.00510 AC XY: 380 AN XY: 74476

African (AFR) AF: 0.0167 AC: 695 AN: 41568

American (AMR) AF: 0.00457 AC: 70 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00173 Hom.: 5

Bravo AF: 0.00611

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00191 AC: 232

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 7 (3)
-	-	3	not specified (3)
-	-	1	Endometrial carcinoma (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0041	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.014	D
Polyphen		0.97	D
Vest4		0.21
MVP		0.95
MPC		0.44
ClinPred		0.034	T
GERP RS		5.5
PromoterAI		-0.036	Neutral
Varity_R		0.20
gMVP		0.22
Mutation Taster		=85/15	polymorphism

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: rs28756993; hg19: chr14-75513142; COSMIC: COSV104587526;