chr14-75013942-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001040108.2(MLH3):​c.*3140C>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 0.00841 in 190,892 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0099 ( 30 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 3_prime_UTR

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: -0.796
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 14-75013942-G-A is Benign according to our data. Variant chr14-75013942-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314346.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00986 (1501/152286) while in subpopulation AFR AF= 0.0332 (1378/41548). AF 95% confidence interval is 0.0317. There are 30 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1501 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH3NM_001040108.2 linkuse as main transcriptc.*3140C>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.*3140C>T 3_prime_UTR_variant 13/135 NM_001040108.2 P1Q9UHC1-1
MLH3ENST00000380968.6 linkuse as main transcriptc.*3140C>T 3_prime_UTR_variant 12/121 Q9UHC1-2

Frequencies

GnomAD3 genomes
AF:
0.00986
AC:
1501
AN:
152168
Hom.:
30
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0333
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00281
Gnomad ASJ
AF:
0.0130
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.0100
GnomAD4 exome
AF:
0.00272
AC:
105
AN:
38606
Hom.:
0
Cov.:
0
AF XY:
0.00262
AC XY:
47
AN XY:
17946
show subpopulations
Gnomad4 AFR exome
AF:
0.0357
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0138
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000870
Gnomad4 OTH exome
AF:
0.00411
GnomAD4 genome
AF:
0.00986
AC:
1501
AN:
152286
Hom.:
30
Cov.:
32
AF XY:
0.00955
AC XY:
711
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0332
Gnomad4 AMR
AF:
0.00281
Gnomad4 ASJ
AF:
0.0130
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00994
Alfa
AF:
0.00496
Hom.:
1
Bravo
AF:
0.0115
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
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
-0.88
CADD
Benign
0.19
DANN
Benign
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs77514025; hg19: chr14-75480645; API