17-37744812-C-G

Variant names:

• chr17-37744812-C-G
• NM_000458.4:c.73G>C
• HNF1B p.Val25Leu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000458.4(HNF1B):​c.73G>C​(p.Val25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V25M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.861
• 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 renal cysts and diabetes syndrome, transient neonatal diabetes mellitus, diabetes mellitus, noninsulin-dependent, unilateral multicystic dysplastic kidney, renal hypomagnesemia 2, medullary sponge kidney, permanent neonatal diabetes mellitus, renal dysplasia, bilateral, renal dysplasia, unilateral.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27247196).

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.73G>C	p.Val25Leu	missense	Exon 1 of 9	NP_000449.1	P35680-1
	HNF1B	NM_001411100.1		c.73G>C	p.Val25Leu	missense	Exon 1 of 8	NP_001398029.1	A0A087WZC2
	HNF1B	NM_001165923.4		c.73G>C	p.Val25Leu	missense	Exon 1 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.73G>C	p.Val25Leu	missense	Exon 1 of 9	ENSP00000480291.1	P35680-1
	HNF1B	ENST00000621123.4	TSL:1	c.73G>C	p.Val25Leu	missense	Exon 1 of 9	ENSP00000482711.1	P35680-2
	HNF1B	ENST00000613727.4	TSL:1	c.73G>C	p.Val25Leu	missense	Exon 1 of 7	ENSP00000477524.1	A0A0C4DGS8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.27	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.86
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.33	T
PromoterAI		0.0038	Neutral
Varity_R		0.29
gMVP		0.42

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-36104803;