NM_000545.8:c.327-42G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000545.8(HNF1A):c.327-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,595,190 control chromosomes in the GnomAD database, including 86,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7146 hom., cov: 33)

Exomes 𝑓: 0.33 ( 78905 hom. )

Consequence

HNF1A
NM_000545.8 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.273

Publications

25 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 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-120988791-G-A is Benign according to our data. Variant chr12-120988791-G-A is described in ClinVar as Benign. ClinVar VariationId is 673535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.327-42G>A	intron_variant	Intron 1 of 9	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.327-42G>A	intron_variant	Intron 1 of 9		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.327-42G>A	intron_variant	Intron 1 of 8		NP_001393844.1
HNF1A	XM_024449168.2 link	c.327-42G>A	intron_variant	Intron 1 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.327-42G>A		intron_variant	Intron 1 of 9	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.294

AC:

44742

AN:

152044

Hom.:

7145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.346

Gnomad AMR

AF:

0.355

Gnomad ASJ

AF:

0.448

Gnomad EAS

AF:

0.410

Gnomad SAS

AF:

0.399

Gnomad FIN

AF:

0.385

Gnomad MID

AF:

0.532

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.313

GnomAD2 exomes

AF:

0.348

AC:

84443

AN:

242538

AF XY:

0.353

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.376

Gnomad ASJ exome

AF:

0.454

Gnomad EAS exome

AF:

0.406

Gnomad FIN exome

AF:

0.376

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.353

GnomAD4 exome

AF:

0.327

AC:

471715

AN:

1443028

Hom.:

78905

Cov.:

AF XY:

0.330

AC XY:

237293

AN XY:

718632

show subpopulations

African (AFR)

AF:

0.156

AC:

5171

AN:

33094

American (AMR)

AF:

0.377

AC:

16554

AN:

43892

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

11895

AN:

25916

East Asian (EAS)

AF:

0.452

AC:

17775

AN:

39368

South Asian (SAS)

AF:

0.405

AC:

34563

AN:

85340

European-Finnish (FIN)

AF:

0.367

AC:

19339

AN:

52722

Middle Eastern (MID)

AF:

0.479

AC:

2750

AN:

5736

European-Non Finnish (NFE)

AF:

0.313

AC:

343552

AN:

1097156

Other (OTH)

AF:

0.336

AC:

20116

AN:

59804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

18348

36695

55043

73390

91738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11228

22456

33684

44912

56140

<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:

0.294

AC:

44744

AN:

152162

Hom.:

7146

Cov.:

AF XY:

0.302

AC XY:

22486

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.163

AC:

6773

AN:

41528

American (AMR)

AF:

0.355

AC:

5429

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.448

AC:

1555

AN:

3472

East Asian (EAS)

AF:

0.410

AC:

2118

AN:

5170

South Asian (SAS)

AF:

0.399

AC:

1921

AN:

4818

European-Finnish (FIN)

AF:

0.385

AC:

4072

AN:

10586

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21733

AN:

67976

Other (OTH)

AF:

0.319

AC:

674

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1664

3328

4992

6656

8320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.310

Hom.:

12268

Bravo

AF:

0.284

Asia WGS

AF:

0.399

AC:

1385

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

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 rs1169294 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.25

(source)

DANN

Benign

0.56

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over