rs754306821

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000545.8(HNF1A):c.923C>T(p.Pro308Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,594,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain risk allele (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 4.76

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.923C>T	p.Pro308Leu	missense_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.923C>T	p.Pro308Leu	missense_variant	Exon 4 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.923C>T	p.Pro308Leu	missense_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.923C>T	p.Pro308Leu	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.923C>T	p.Pro308Leu	missense_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD2 exomes

AF:

0.0000281

AC:

AN:

213210

AF XY:

0.0000348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000971

AC:

AN:

1441854

Hom.:

Cov.:

AF XY:

0.00000979

AC XY:

AN XY:

715308

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33308

Gnomad4 AMR exome

AF:

0.000122

AC:

AN:

41006

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25510

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39150

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

83400

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

51822

Gnomad4 NFE exome

AF:

0.00000816

AC:

AN:

1102288

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

59628

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000241266

AN:

0.0000241266

Gnomad4 AMR

AF:

0.000131

AC:

0.000130856

AN:

0.000130856

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000108

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant seen in 1 affected patient in HGMD. Max MAF of 0.03% in ExAC. -

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

Nov 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Sep 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 18003757). This sequence change replaces proline with leucine at codon 308 of the HNF1A protein (p.Pro308Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs754306821, ExAC 0.03%). ClinVar contains an entry for this variant (Variation ID: 402948). 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 expected to disrupt HNF1A protein function. 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. -

Maturity-onset diabetes of the young type 3

Uncertain:1

Oct 15, 2024

Genetics Department, Catlab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.923C>T variant in the HNF1A gene has not been previously described in patients with diabetes MODY to our knowledge. The variants has a very low frequency in gnomAD 4.0 (AF=1.0664e-05) (PM2) and REVEL value is 0.687 (PP3). With all the available evidence, the variant is classified as of unknown significance. -

Maturity onset diabetes mellitus in young

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain risk allele

Review Status:criteria provided, single submitter

Collection Method:research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs754306821 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D;T;.

Eigen

Benign

-0.023

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.62

D;D;D;D

MetaSVM

Uncertain

0.76

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.4

N;.;N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.024

D;.;D;D

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.90

.;.;.;P

Vest4

0.43

MutPred

0.67

Loss of glycosylation at P308 (P = 0.0127);Loss of glycosylation at P308 (P = 0.0127);Loss of glycosylation at P308 (P = 0.0127);Loss of glycosylation at P308 (P = 0.0127);

MVP

0.98

MPC

0.21

ClinPred

0.22

GERP RS

4.7

gMVP

0.88

Mutation Taster

=1/99

disease causing

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