NM_000458.4:c.226G>A

Variant names:

• chr17-37744659-C-T
• rs144425830
• NM_000458.4:c.226G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000458.4(HNF1B):​c.226G>A​(p.Gly76Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G76C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.68
• Publications: 14 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000458.4
• 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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.226G>A	p.Gly76Ser	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.226G>A	p.Gly76Ser	missense_variant	Exon 1 of 9	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.226G>A	p.Gly76Ser	missense_variant	Exon 1 of 9	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.226G>A	p.Gly76Ser	missense_variant	Exon 1 of 7	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.226G>A	p.Gly76Ser	missense_variant	Exon 1 of 8	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;T;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;M;.;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	0.10	T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.35
MutPred		0.53		Gain of phosphorylation at G76 (P = 0.0101);Gain of phosphorylation at G76 (P = 0.0101);Gain of phosphorylation at G76 (P = 0.0101);Gain of phosphorylation at G76 (P = 0.0101);Gain of phosphorylation at G76 (P = 0.0101);Gain of phosphorylation at G76 (P = 0.0101);
MVP		0.95
ClinPred		0.97	D
GERP RS		5.1
PromoterAI		-0.0078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.55

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: rs144425830; hg19: chr17-36104650;