Genetic Variant NM_001040108.2:c.3570+384T>A (chr14-75039527-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.250

Publications

10 publications found

Variant links:

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

MLH3 links:

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ACMG classification

Classification was made for transcript

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

Sel.	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	Q9UHC1-1
	MLH3	NM_014381.3		c.3570+384T>A		intron	N/A	NP_055196.2	Q9UHC1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH3	ENST00000355774.7	TSL:5 MANE Select	c.3570+384T>A	intron	N/A	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6	TSL:1	c.3570+384T>A	intron	N/A	ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000930871.1		c.3570+384T>A	intron	N/A	ENSP00000600930.1

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50555

AN:

151676

Hom.:

10326

Cov.:

show subpopulations

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.:

AF XY:

0.334

AC XY:

24807

AN XY:

74172

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1403

2806

4208

5611

7014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

496

992

1488

1984

2480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

DANN

Benign

0.63

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over