NM_000458.4:c.545-2704G>C

Variant names:

• chr17-37736525-C-G
• rs757210
• NM_000458.4:c.545-2704G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000458.4(HNF1B):​c.545-2704G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 152,054 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.018 (43 hom., cov: 31)
• Consequence: HNF1B NM_000458.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 124 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (Cadd=0.047).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0178 (2706/152054) while in subpopulation NFE AF = 0.0241 (1638/67982). AF 95% confidence interval is 0.0231. There are 43 homozygotes in GnomAd4. There are 1331 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2706 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	NM_000458.4	MANE Select	c.545-2704G>C		intron	N/A	NP_000449.1
	HNF1B	NM_001411100.1		c.545-2704G>C		intron	N/A	NP_001398029.1
	HNF1B	NM_001165923.4		c.545-2782G>C		intron	N/A	NP_001159395.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.545-2704G>C		intron	N/A	ENSP00000480291.1
	HNF1B	ENST00000621123.4	TSL:1	c.545-2782G>C		intron	N/A	ENSP00000482711.1
	HNF1B	ENST00000613727.4	TSL:1	c.545-2782G>C		intron	N/A	ENSP00000477524.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2706 AN: 151936 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00462

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0173

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0178 AC: 2706 AN: 152054 Hom.: 43 Cov.: 31 AF XY: 0.0179 AC XY: 1331 AN XY: 74344

African (AFR) AF: 0.00461 AC: 191 AN: 41454

American (AMR) AF: 0.0164 AC: 251 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4824

European-Finnish (FIN) AF: 0.0345 AC: 364 AN: 10564

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0241 AC: 1638 AN: 67982

Other (OTH) AF: 0.0171 AC: 36 AN: 2106

Alfa AF: 0.000216 Hom.: 40146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
CADD	Benign	0.047
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs757210;