chr12-120999627-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1768C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 590(p.(Arg583Gly)) of NM_000545.8. This variant has a minor allele frequency of 0.000009 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). In summary, c.1768C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386973441/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense, splice_region

Scores

11
7
Splicing: ADA: 0.9989
2

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 2.66
Variant links:
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF1ANM_000545.8 linkc.1768G>A p.Val590Met missense_variant, splice_region_variant Exon 9 of 10 ENST00000257555.11 NP_000536.6 P20823E0YMI7
HNF1ANM_001306179.2 linkc.1789G>A p.Val597Met missense_variant, splice_region_variant Exon 9 of 10 NP_001293108.2 P20823E0YMI7
HNF1ANM_001406915.1 linkc.1576G>A p.Val526Met missense_variant, splice_region_variant Exon 8 of 9 NP_001393844.1
HNF1AXM_024449168.2 linkc.1861G>A p.Val621Met missense_variant, splice_region_variant Exon 8 of 9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkc.1768G>A p.Val590Met missense_variant, splice_region_variant Exon 9 of 10 1 NM_000545.8 ENSP00000257555.5 A0A0A0MQU7

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000420
AC:
1
AN:
238240
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
130248
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000949
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1456676
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
724638
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJan 16, 2017- -
Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelApr 17, 2022The c.1768C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 590(p.(Arg583Gly)) of NM_000545.8. This variant has a minor allele frequency of 0.000009 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). In summary, c.1768C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 30, 2024This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 590 of the HNF1A protein (p.Val590Met). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 33477506). ClinVar contains an entry for this variant (Variation ID: 447484). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Probably Damaging". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
.;T;.;T;.
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.29
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.79
T;T;T;T;T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.24
T;T;T;T;T
MetaSVM
Uncertain
0.15
D
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.77
N;.;.;N;N
REVEL
Uncertain
0.44
Sift
Uncertain
0.017
D;.;.;D;D
Sift4G
Uncertain
0.060
T;T;T;T;T
Polyphen
0.068
.;.;.;.;B
Vest4
0.15
MutPred
0.63
.;.;.;.;Gain of glycosylation at P595 (P = 0.0678);
MVP
0.83
MPC
0.53
ClinPred
0.25
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
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: rs1168108747; hg19: chr12-121437430; API