chr12-120978993-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: -0.679

Publications

2 publications found

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]

HNF1A links:

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

HNF1A-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
HNF1A	NM_000545.8 link	c.225C>A	p.Asp75Glu	missense_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.225C>A	p.Asp75Glu	missense_variant	Exon 1 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.225C>A	p.Asp75Glu	missense_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.225C>A	p.Asp75Glu	missense_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.225C>A	p.Asp75Glu	missense_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000425

AC:

AN:

235122

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1456572

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.0000229

AC:

AN:

43642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25940

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.00

AC:

AN:

85434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1109754

Other (OTH)

AF:

0.0000166

AC:

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:1

Apr 08, 2022

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

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. -

not provided

Uncertain:1

Mar 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported 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

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

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

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Uncertain

0.19

PhyloP100

-0.68

PrimateAI

Uncertain

0.59

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

GERP RS

-0.11

PromoterAI

-0.017

Neutral

(source)

gMVP

0.67

Mutation Taster

=5/95

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over