dbSNP rs1183910: HNF1A:c.326+3910G>A (chr12-120983004-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000545.8(HNF1A):c.326+3910G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 152,090 control chromosomes in the GnomAD database, including 6,826 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6826 hom., cov: 32)

Consequence

HNF1A
NM_000545.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.03

Publications

80 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.326+3910G>A	intron	N/A	NP_000536.6
HNF1A	NM_001306179.2		c.326+3910G>A	intron	N/A	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.326+3910G>A	intron	N/A	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.326+3910G>A	intron	N/A	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.326+3910G>A	intron	N/A	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000535955.5	TSL:1	n.42+4312G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.282

AC:

42840

AN:

151972

Hom.:

6824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.452

Gnomad EAS

AF:

0.398

Gnomad SAS

AF:

0.395

Gnomad FIN

AF:

0.387

Gnomad MID

AF:

0.532

Gnomad NFE

AF:

0.319

Gnomad OTH

AF:

0.306

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.282

AC:

42846

AN:

152090

Hom.:

6826

Cov.:

AF XY:

0.291

AC XY:

21633

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.125

AC:

5186

AN:

41494

American (AMR)

AF:

0.341

AC:

5212

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

1567

AN:

3470

East Asian (EAS)

AF:

0.398

AC:

2054

AN:

5160

South Asian (SAS)

AF:

0.395

AC:

1901

AN:

4812

European-Finnish (FIN)

AF:

0.387

AC:

4089

AN:

10560

Middle Eastern (MID)

AF:

0.527

AC:

155

AN:

294

European-Non Finnish (NFE)

AF:

0.319

AC:

21696

AN:

67994

Other (OTH)

AF:

0.312

AC:

660

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1499

2998

4498

5997

7496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.312

Hom.:

28133

Bravo

AF:

0.269

Asia WGS

AF:

0.388

AC:

1346

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.0020

(source)

DANN

Benign

0.68

PhyloP100

-2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over