17-37731814-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000458.4(HNF1B):​c.826C>G​(p.Arg276Gly) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.08
• Publications: 0 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-37731813-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 635641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 72 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: 2.0703 (below the threshold of 3.09). GenCC associations: The gene is linked to unilateral multicystic dysplastic kidney, renal dysplasia, unilateral, renal cysts and diabetes syndrome, medullary sponge kidney, renal hypomagnesemia 2, renal dysplasia, bilateral, diabetes mellitus, noninsulin-dependent, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 17-37731814-G-C is Pathogenic according to our data. Variant chr17-37731814-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 635640.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	NM_000458.4	MANE Select	c.826C>G	p.Arg276Gly	missense	Exon 4 of 9	NP_000449.1
	HNF1B	NM_001411100.1		c.826C>G	p.Arg276Gly	missense	Exon 4 of 8	NP_001398029.1
	HNF1B	NM_001165923.4		c.748C>G	p.Arg250Gly	missense	Exon 4 of 9	NP_001159395.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.826C>G	p.Arg276Gly	missense	Exon 4 of 9	ENSP00000480291.1
	HNF1B	ENST00000621123.4	TSL:1	c.748C>G	p.Arg250Gly	missense	Exon 4 of 9	ENSP00000482711.1
	HNF1B	ENST00000613727.4	TSL:1	c.748C>G	p.Arg250Gly	missense	Exon 4 of 7	ENSP00000477524.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cysts and diabetes syndrome Pathogenic:1

Jul 06, 2019

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

HNF1B-related disorder Pathogenic:1

Mar 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HNF1B c.826C>G variant is predicted to result in the amino acid substitution p.Arg276Gly. This variant has been reported in individuals affected with HNF1B-related disorders, and functional studies support its pathogenicity (Bellanne-Chantelot et al. 2005. PubMed ID: 16249435; Ferrè et al. 2013. PubMed ID: 24204001). An alternate missense variant at the same amino acid position has also been reported as a causative change, including as a de novo finding (Pinon et al. 2019. PubMed ID: 30791938; Edghill et al. 2006. PubMed ID: 15930087). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.93	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.96
MutPred		0.88		Loss of loop (P = 0.0203)
MVP		0.99
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.68
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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;