rs202180554

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.225C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to glutamate at codon 75 (p.(Asp75Glu)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%; therefore, PP4 could not be applied (internal lab contributors). In summary, c.225C>A 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/CA386953852/MONDO:0015967/017

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

3
6
9

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: -0.679
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/exons MANE Protein UniProt
HNF1ANM_000545.8 linkuse as main transcriptc.225C>A p.Asp75Glu missense_variant 1/10 ENST00000257555.11 NP_000536.6 P20823E0YMI7
HNF1ANM_001306179.2 linkuse as main transcriptc.225C>A p.Asp75Glu missense_variant 1/10 NP_001293108.2 P20823E0YMI7
HNF1ANM_001406915.1 linkuse as main transcriptc.225C>A p.Asp75Glu missense_variant 1/9 NP_001393844.1
HNF1AXM_024449168.2 linkuse as main transcriptc.225C>A p.Asp75Glu missense_variant 1/9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.225C>A p.Asp75Glu missense_variant 1/101 NM_000545.8 ENSP00000257555.5 A0A0A0MQU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000425
AC:
1
AN:
235122
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
127988
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000303
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000481
AC:
7
AN:
1456572
Hom.:
0
Cov.:
35
AF XY:
0.00000414
AC XY:
3
AN XY:
724152
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000229
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:
0.00000451
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelApr 08, 2022The c.225C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to glutamate at codon 75 (p.(Asp75Glu)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%; therefore, PP4 could not be applied (internal lab contributors). In summary, c.225C>A 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 testingGeneDxMar 04, 2024Reported in a patient with MODY in published literature; however, clinical data is not available (PMID: 18003757); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18003757) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.14
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.48
.;T;T;D;T;.
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.70
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.20
T;T;T;T;T;T
MetaSVM
Uncertain
0.19
D
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.25
N;.;.;N;N;N
REVEL
Uncertain
0.56
Sift
Benign
0.40
T;.;.;T;T;T
Sift4G
Benign
0.28
T;T;T;T;T;T
Polyphen
0.74
.;.;.;.;.;P
Vest4
0.17
MutPred
0.68
Gain of relative solvent accessibility (P = 0.2629);Gain of relative solvent accessibility (P = 0.2629);Gain of relative solvent accessibility (P = 0.2629);Gain of relative solvent accessibility (P = 0.2629);Gain of relative solvent accessibility (P = 0.2629);Gain of relative solvent accessibility (P = 0.2629);
MVP
0.97
MPC
0.30
ClinPred
0.35
T
GERP RS
-0.11
gMVP
0.67

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: rs202180554; hg19: chr12-121416796; API