17-37744584-C-G

Variant names:

• chr17-37744584-C-G
• rs121918671
• NM_000458.4:c.301G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP2 PP3_Moderate BS2

The NM_000458.4(HNF1B):​c.301G>C​(p.Glu101Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000962 in 1,454,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98
• Publications: 6 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), G2P, Genomics England PanelApp, Orphanet, ClinGen
• 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: Likely_benign. The variant received -1 ACMG points.

• 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, 0.867
• BS2: High AC in GnomAdExome4 at 14 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.301G>C	p.Glu101Gln	missense	Exon 1 of 9	NP_000449.1	P35680-1
	HNF1B	NM_001411100.1		c.301G>C	p.Glu101Gln	missense	Exon 1 of 8	NP_001398029.1	A0A087WZC2
	HNF1B	NM_001165923.4		c.301G>C	p.Glu101Gln	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.301G>C	p.Glu101Gln	missense	Exon 1 of 9	ENSP00000480291.1	P35680-1
	HNF1B	ENST00000621123.4	TSL:1	c.301G>C	p.Glu101Gln	missense	Exon 1 of 9	ENSP00000482711.1	P35680-2
	HNF1B	ENST00000613727.4	TSL:1	c.301G>C	p.Glu101Gln	missense	Exon 1 of 7	ENSP00000477524.1	A0A0C4DGS8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245210 AF XY: 0.00000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000962 AC: 14 AN: 1454878 Hom.: 0 Cov.: 35 AF XY: 0.00000967 AC XY: 7 AN XY: 724090

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.0
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.090	T
Polyphen		0.69	P
Vest4		0.51
MutPred		0.84		Loss of loop (P = 0.1242)
MVP		0.78
ClinPred		0.94	D
GERP RS		3.2
PromoterAI		-0.034	Neutral
Varity_R		0.40
gMVP		0.74
Mutation Taster		=66/34	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: rs121918671; hg19: chr17-36104575;