rs139107479
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000458.4(HNF1B):c.73G>T(p.Val25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,613,566 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0013 ( 4 hom., cov: 33)
Exomes 𝑓: 0.0022 ( 77 hom. )
Consequence
HNF1B
NM_000458.4 missense
NM_000458.4 missense
Scores
1
4
9
Clinical Significance
Conservation
PhyloP100: 0.861
Genes affected
HNF1B (HGNC:11630): (HNF1 homeobox B) This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.008750111).
BP6
?
Variant 17-37744812-C-A is Benign according to our data. Variant chr17-37744812-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36852.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=7, Uncertain_significance=1}. Variant chr17-37744812-C-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00125 (191/152290) while in subpopulation SAS AF= 0.0352 (170/4826). AF 95% confidence interval is 0.0309. There are 4 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High AC in GnomAd at 191 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1B | NM_000458.4 | c.73G>T | p.Val25Leu | missense_variant | 1/9 | ENST00000617811.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1B | ENST00000617811.5 | c.73G>T | p.Val25Leu | missense_variant | 1/9 | 1 | NM_000458.4 | ||
HNF1B | ENST00000621123.4 | c.73G>T | p.Val25Leu | missense_variant | 1/9 | 1 | P1 | ||
HNF1B | ENST00000613727.4 | c.73G>T | p.Val25Leu | missense_variant | 1/7 | 1 | |||
HNF1B | ENST00000614313.4 | c.73G>T | p.Val25Leu | missense_variant | 1/8 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00126 AC: 191AN: 152172Hom.: 4 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
191
AN:
152172
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00460 AC: 1153AN: 250822Hom.: 20 AF XY: 0.00610 AC XY: 828AN XY: 135822
GnomAD3 exomes
AF:
AC:
1153
AN:
250822
Hom.:
AF XY:
AC XY:
828
AN XY:
135822
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00219 AC: 3197AN: 1461276Hom.: 77 Cov.: 35 AF XY: 0.00312 AC XY: 2266AN XY: 726966
GnomAD4 exome
AF:
AC:
3197
AN:
1461276
Hom.:
Cov.:
35
AF XY:
AC XY:
2266
AN XY:
726966
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00125 AC: 191AN: 152290Hom.: 4 Cov.: 33 AF XY: 0.00180 AC XY: 134AN XY: 74456
GnomAD4 genome
?
AF:
AC:
191
AN:
152290
Hom.:
Cov.:
33
AF XY:
AC XY:
134
AN XY:
74456
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
?
AF:
AC:
646
Asia WGS
AF:
AC:
68
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 17, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 27, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Maturity onset diabetes mellitus in young Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in HNF1B gene are generally associated with early onset diabetes and pancreatic atrophy. It is also associated with multiple renal manifestations including renal cysts, Tubulointerstitial disease, glomerulocystic disease, renal hypoplasia, hypomagnesemia. However, no sufficient evidence is found for the role of this particular variant (rs139107479) of HNF1B in Diabetes Mellitus or MODY yet. - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2017 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Renal cysts and diabetes syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | HNF1B: BS1, BS2 - |
Nonpapillary renal cell carcinoma Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.;T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
P;.;.;.;.;.
Vest4
MutPred
Loss of methylation at K23 (P = 0.102);Loss of methylation at K23 (P = 0.102);Loss of methylation at K23 (P = 0.102);Loss of methylation at K23 (P = 0.102);Loss of methylation at K23 (P = 0.102);Loss of methylation at K23 (P = 0.102);
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at