chr14-75013934-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040108.2(MLH3):​c.*3148A>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 0.421 in 194,262 control chromosomes in the GnomAD database, including 17,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 14021 hom., cov: 32)
Exomes 𝑓: 0.41 ( 3795 hom. )

Consequence

MLH3
NM_001040108.2 3_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.97
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.94).
BP6
Variant 14-75013934-T-C is Benign according to our data. Variant chr14-75013934-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 314345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH3NM_001040108.2 linkuse as main transcriptc.*3148A>G 3_prime_UTR_variant 13/13 ENST00000355774.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH3ENST00000355774.7 linkuse as main transcriptc.*3148A>G 3_prime_UTR_variant 13/135 NM_001040108.2 P1Q9UHC1-1
MLH3ENST00000380968.6 linkuse as main transcriptc.*3148A>G 3_prime_UTR_variant 12/121 Q9UHC1-2

Frequencies

GnomAD3 genomes
AF:
0.423
AC:
64288
AN:
151936
Hom.:
14006
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.406
Gnomad AMI
AF:
0.473
Gnomad AMR
AF:
0.353
Gnomad ASJ
AF:
0.485
Gnomad EAS
AF:
0.155
Gnomad SAS
AF:
0.461
Gnomad FIN
AF:
0.446
Gnomad MID
AF:
0.519
Gnomad NFE
AF:
0.459
Gnomad OTH
AF:
0.437
GnomAD4 exome
AF:
0.412
AC:
17383
AN:
42208
Hom.:
3795
Cov.:
0
AF XY:
0.412
AC XY:
8028
AN XY:
19492
show subpopulations
Gnomad4 AFR exome
AF:
0.433
Gnomad4 AMR exome
AF:
0.353
Gnomad4 ASJ exome
AF:
0.488
Gnomad4 EAS exome
AF:
0.168
Gnomad4 SAS exome
AF:
0.492
Gnomad4 FIN exome
AF:
0.600
Gnomad4 NFE exome
AF:
0.467
Gnomad4 OTH exome
AF:
0.444
GnomAD4 genome
AF:
0.423
AC:
64338
AN:
152054
Hom.:
14021
Cov.:
32
AF XY:
0.421
AC XY:
31324
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.406
Gnomad4 AMR
AF:
0.352
Gnomad4 ASJ
AF:
0.485
Gnomad4 EAS
AF:
0.155
Gnomad4 SAS
AF:
0.461
Gnomad4 FIN
AF:
0.446
Gnomad4 NFE
AF:
0.459
Gnomad4 OTH
AF:
0.444
Alfa
AF:
0.448
Hom.:
2501
Bravo
AF:
0.411
Asia WGS
AF:
0.364
AC:
1265
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxFeb 18, 2020This variant is associated with the following publications: (PMID: 29516665) -
Vanishing white matter disease Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.94
CADD
Benign
0.032
DANN
Benign
0.28

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs108621; hg19: chr14-75480637; API