rs1555833051

Variant names:

• chr17-37744623-T-C
• rs1555833051
• NM_000458.4:c.262A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000458.4(HNF1B):​c.262A>G​(p.Thr88Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain risk allele (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 4.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.262A>G	p.Thr88Ala	missense_variant	Exon 1 of 9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.262A>G	p.Thr88Ala	missense_variant	Exon 1 of 9	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.262A>G	p.Thr88Ala	missense_variant	Exon 1 of 9	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.262A>G	p.Thr88Ala	missense_variant	Exon 1 of 7	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.262A>G	p.Thr88Ala	missense_variant	Exon 1 of 8	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

HNF1B-related disorder Uncertain:1

Jun 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HNF1B c.262A>G variant is predicted to result in the amino acid substitution p.Thr88Ala. This variant has been reported in an individual with type 2 diabetes however, in vitro functional assays suggest this variant has HNF-1B activity similar to control (Figure 3, Pavithram et al. 2024. PubMed ID: 38575066). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Monogenic diabetes Uncertain:1

Jun 26, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG Criteria:PP3 (7 predictors), BP4 (2 predictors), PM2 (absent in database) -

Maturity onset diabetes mellitus in young Other:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain risk allele

Review Status: criteria provided, single submitter

Collection Method: research

HNF1B gene mutations are associated with early onset diabetes and pancreatic atrophy. It is also associated with multiple renal manifestations including renal cysts, Tubulointerstitial disease, glomerulocystic disease, renal hypoplasia, hypomagnesemia. However no sufficient evidence is found to ascertain the role of this particular variant rs1555833051, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;.;T;T;.;.
Eigen	Benign	0.089
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.4	L;L;.;.;.;.
PrimateAI	Uncertain	0.71	T
Sift4G	Uncertain	0.059	T;T;T;D;T;D
Polyphen		0.66	P;.;.;.;.;.
Vest4		0.38
MutPred		0.63		Loss of phosphorylation at T88 (P = 0.0325);Loss of phosphorylation at T88 (P = 0.0325);Loss of phosphorylation at T88 (P = 0.0325);Loss of phosphorylation at T88 (P = 0.0325);Loss of phosphorylation at T88 (P = 0.0325);Loss of phosphorylation at T88 (P = 0.0325);
MVP		0.82
ClinPred		0.86	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs1555833051; hg19: chr17-36104614;