rs202180554

chr12-120978993-C-Achr12-120978993-C-Gchr12-120978993-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000545.8(HNF1A):c.225C>A(p.Asp75Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,456,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. D75D) has been classified as Benign.

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:1

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]

HNF1A links:

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

HNF1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20186102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNF1A	NM_000545.8 linkuse as main transcript	c.225C>A	p.Asp75Glu	missense_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2 linkuse as main transcript	c.225C>A	p.Asp75Glu	missense_variant	1/10
HNF1A	NM_001406915.1 linkuse as main transcript	c.225C>A	p.Asp75Glu	missense_variant	1/9
HNF1A	XM_024449168.2 linkuse as main transcript	c.225C>A	p.Asp75Glu	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.225C>A	p.Asp75Glu	missense_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1 linkuse as main transcript	n.128+1651G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000425

AC:

AN:

235122

Hom.:

AF XY:

0.00

AC XY:

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:

AN:

1456572

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 08, 2022

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. -

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

Dann

Uncertain

0.98

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

MutationTaster

Benign

1.0

D;N;N;N;N

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over