chr14-75014117-G-A

Variant summary

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

The NM_001040108.2(MLH3):​c.*2965C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 176,456 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 230 hom., cov: 32)
Exomes 𝑓: 0.0041 ( 3 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: -0.0460
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=-0.87).
BP6
Variant 14-75014117-G-A is Benign according to our data. Variant chr14-75014117-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0977 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH3NM_001040108.2 linkuse as main transcriptc.*2965C>T 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.*2965C>T 3_prime_UTR_variant 13/135 NM_001040108.2 P1Q9UHC1-1
MLH3ENST00000380968.6 linkuse as main transcriptc.*2965C>T 3_prime_UTR_variant 12/121 Q9UHC1-2

Frequencies

GnomAD3 genomes
AF:
0.0288
AC:
4378
AN:
152170
Hom.:
230
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.100
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0102
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.0206
GnomAD4 exome
AF:
0.00414
AC:
100
AN:
24168
Hom.:
3
Cov.:
0
AF XY:
0.00301
AC XY:
34
AN XY:
11278
show subpopulations
Gnomad4 AFR exome
AF:
0.0995
Gnomad4 AMR exome
AF:
0.00940
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000204
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000142
Gnomad4 OTH exome
AF:
0.00829
GnomAD4 genome
AF:
0.0288
AC:
4383
AN:
152288
Hom.:
230
Cov.:
32
AF XY:
0.0277
AC XY:
2062
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.100
Gnomad4 AMR
AF:
0.0102
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000830
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.0203
Alfa
AF:
0.0357
Hom.:
31
Bravo
AF:
0.0333
Asia WGS
AF:
0.00318
AC:
11
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 13, 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
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Vanishing white matter disease Benign:1
Likely 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
-0.87
CADD
Benign
1.7
DANN
Benign
0.53

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: rs10134636; hg19: chr14-75480820; API