NM_000545.8:c.901G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000545.8(HNF1A):c.901G>A(p.Ala301Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,600,064 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.92

Publications

6 publications found

Variant links:

COSMIC-nc: COSV109409886

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 Gene-Disease associations (from GenCC):

monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
type 1 diabetes mellitus 20
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
maturity-onset diabetes of the young type 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hyperinsulinism due to HNF1A deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nonpapillary renal cell carcinoma
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23773482).

BS2

High AC in GnomAdExome4 at 25 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.901G>A	p.Ala301Thr	missense_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.901G>A	p.Ala301Thr	missense_variant	Exon 4 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.901G>A	p.Ala301Thr	missense_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.901G>A	p.Ala301Thr	missense_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.901G>A	p.Ala301Thr	missense_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000451

AC:

AN:

221838

AF XY:

0.0000417

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000322

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.0000596

Gnomad FIN exome

AF:

0.0000530

Gnomad NFE exome

AF:

0.0000506

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1447908

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

719076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.0000713

AC:

AN:

42070

Ashkenazi Jewish (ASJ)

AF:

0.0000390

AC:

AN:

25614

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39318

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84194

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1105724

Other (OTH)

AF:

0.0000334

AC:

AN:

59810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000488

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 22, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 301 of the HNF1A protein (p.Ala301Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 10027593, 19336507, 37396188). ClinVar contains an entry for this variant (Variation ID: 586796). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect HNF1A function (PMID: 37396188). 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. -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Molecular Genetics, Madras Diabetes Research Foundation

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.43

.;T;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Uncertain

-0.0046

PhyloP100

1.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.23

N;.;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.50

T;.;T;T

Sift4G

Benign

0.77

T;T;T;T

Polyphen

0.037

.;.;.;B

Vest4

0.25

MutPred

0.53

Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);

MVP

0.96

MPC

0.12

ClinPred

0.034

GERP RS

3.8

gMVP

0.72

Mutation Taster

=1/99

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over