dbSNP rs140781855: HNF1B:p.Pro471Pro (chr17-37701104-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000458.4(HNF1B):c.1413C>T(p.Pro471Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000611 in 1,552,674 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 6 hom. )

Consequence

HNF1B
NM_000458.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -3.18

Publications

2 publications found

Variant links:

Genes affected

HNF1B (HGNC:11630): (HNF1 homeobox B) This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

HNF1B Gene-Disease associations (from GenCC):

renal cysts and diabetes syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, ClinGen
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
permanent neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
transient neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
medullary sponge kidney
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal dysplasia, bilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal dysplasia, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal hypomagnesemia 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
unilateral multicystic dysplastic kidney
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNF1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 17-37701104-G-A is Benign according to our data. Variant chr17-37701104-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.18 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00278 (424/152256) while in subpopulation AFR AF = 0.00934 (388/41546). AF 95% confidence interval is 0.00857. There are 4 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 424 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000458.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1B	NM_000458.4	MANE Select	c.1413C>T	p.Pro471Pro	synonymous	Exon 7 of 9	NP_000449.1	P35680-1
HNF1B	NM_001411100.1		c.1413C>T	p.Pro471Pro	synonymous	Exon 7 of 8	NP_001398029.1	A0A087WZC2
HNF1B	NM_001165923.4		c.1335C>T	p.Pro445Pro	synonymous	Exon 7 of 9	NP_001159395.1	E0YMJ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.1413C>T	p.Pro471Pro	synonymous	Exon 7 of 9	ENSP00000480291.1	P35680-1
HNF1B	ENST00000621123.4	TSL:1	c.1335C>T	p.Pro445Pro	synonymous	Exon 7 of 9	ENSP00000482711.1	P35680-2
HNF1B	ENST00000613727.4	TSL:1	c.1261+3813C>T		intron	N/A	ENSP00000477524.1	A0A0C4DGS8

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

424

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00937

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.000671

AC:

107

AN:

159492

AF XY:

0.000441

show subpopulations

Gnomad AFR exome

AF:

0.00898

Gnomad AMR exome

AF:

0.000600

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000145

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.000375

AC:

525

AN:

1400418

Hom.:

Cov.:

AF XY:

0.000321

AC XY:

222

AN XY:

690896

show subpopulations

African (AFR)

AF:

0.0106

AC:

338

AN:

31802

American (AMR)

AF:

0.000612

AC:

AN:

35950

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25200

East Asian (EAS)

AF:

0.0000554

AC:

AN:

36080

South Asian (SAS)

AF:

0.0000378

AC:

AN:

79322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49390

Middle Eastern (MID)

AF:

0.00146

AC:

AN:

4782

European-Non Finnish (NFE)

AF:

0.0000889

AC:

AN:

1079890

Other (OTH)

AF:

0.000965

AC:

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00278

AC:

424

AN:

152256

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00934

AC:

388

AN:

41546

American (AMR)

AF:

0.00124

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68016

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00106

Hom.:

Bravo

AF:

0.00315

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Maturity-onset diabetes of the young (2)

HNF1B-related disorder (1)

Nonpapillary renal cell carcinoma (1)

Renal cysts and diabetes syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

3.8

(source)

DANN

Benign

0.61

PhyloP100

-3.2

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over