Genetic Variant NM_000458.4:c.*659G>A (chr17-37686713-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000458.4(HNF1B):c.*659G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 172,902 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

HNF1B
NM_000458.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.518

Publications

1 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:

ENSG00000277688 (HGNC:):

ENSG00000277688 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=-0.8).

BP6

Variant 17-37686713-C-T is Benign according to our data. Variant chr17-37686713-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 892033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00194 (295/152240) while in subpopulation AFR AF = 0.00657 (273/41528). AF 95% confidence interval is 0.00593. There are 0 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 295 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	Effect	Exon Rank	Protein	UniProt
HNF1B	NM_000458.4	MANE Select	c.*659G>A	3_prime_UTR	Exon 9 of 9	NP_000449.1	P35680-1
HNF1B	NM_001411100.1		c.*567G>A	3_prime_UTR	Exon 8 of 8	NP_001398029.1	A0A087WZC2
HNF1B	NM_001165923.4		c.*659G>A	3_prime_UTR	Exon 9 of 9	NP_001159395.1	E0YMJ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.*659G>A	3_prime_UTR	Exon 9 of 9	ENSP00000480291.1	P35680-1
HNF1B	ENST00000904917.1		c.*659G>A	3_prime_UTR	Exon 9 of 9	ENSP00000574976.1
HNF1B	ENST00000904916.1		c.*659G>A	3_prime_UTR	Exon 8 of 8	ENSP00000574975.1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

295

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00659

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

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:

0.0000441

Gnomad OTH

AF:

0.00192

GnomAD4 exome

AF:

0.0000484

AC:

AN:

20662

Hom.:

Cov.:

AF XY:

0.0000904

AC XY:

AN XY:

11056

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

432

American (AMR)

AF:

0.00

AC:

AN:

3420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

232

East Asian (EAS)

AF:

0.00

AC:

AN:

1486

South Asian (SAS)

AF:

0.00

AC:

AN:

3118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

10694

Other (OTH)

AF:

0.00

AC:

AN:

862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00194

AC:

295

AN:

152240

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00657

AC:

273

AN:

41528

American (AMR)

AF:

0.000916

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00118

Hom.:

Bravo

AF:

0.00212

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Maturity-onset diabetes of the young (1)

Renal cysts and diabetes syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.6

(source)

DANN

Benign

0.59

PhyloP100

-0.52

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over