rs121918672

Variant names:

• chr17-37731814-G-A
• rs121918672
• NM_000458.4:c.826C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-37731814-G-A
• chr17-37731814-G-C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000458.4(HNF1B):​c.826C>T​(p.Arg276*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001427158: Functional analysis showed that the mutant allele produces inactive protein (Furuta, H. et al., 2002). In addition, p.(Arg276*) caused significant decrease in glucose-stimulated insulin secretion in MIN6 cells (Fujimoto, K. et al., 2007)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.08
• Publications: 13 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001427158: Functional analysis showed that the mutant allele produces inactive protein (Furuta, H. et al., 2002). In addition, p.(Arg276*) caused significant decrease in glucose-stimulated insulin secretion in MIN6 cells (Fujimoto, K. et al., 2007).; SCV002072962: Functional studies reveal a damaging effect.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-37731814-G-A is Pathogenic according to our data. Variant chr17-37731814-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	NM_000458.4	MANE Select	c.826C>T	p.Arg276*	stop_gained	Exon 4 of 9	NP_000449.1	P35680-1
	HNF1B	NM_001411100.1		c.826C>T	p.Arg276*	stop_gained	Exon 4 of 8	NP_001398029.1	A0A087WZC2
	HNF1B	NM_001165923.4		c.748C>T	p.Arg250*	stop_gained	Exon 4 of 9	NP_001159395.1	E0YMJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.826C>T	p.Arg276*	stop_gained	Exon 4 of 9	ENSP00000480291.1	P35680-1
	HNF1B	ENST00000621123.4	TSL:1	c.748C>T	p.Arg250*	stop_gained	Exon 4 of 9	ENSP00000482711.1	P35680-2
	HNF1B	ENST00000613727.4	TSL:1	c.748C>T	p.Arg250*	stop_gained	Exon 4 of 7	ENSP00000477524.1	A0A0C4DGS8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Renal cysts and diabetes syndrome (5)
3	-	-	not provided (3)
1	-	-	Autosomal dominant medullary cystic kidney disease with or without hyperuricemia (1)
1	-	-	Maturity-onset diabetes of the young (1)
1	-	-	Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome;CN074294:Nonpapillary renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.1
Vest4		0.96
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918672; hg19: chr17-36091805;