NM_000458.4:c.*99C>A

Variant names:

• chr17-37687273-G-T
• rs2229295
• NM_000458.4:c.*99C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000458.4(HNF1B):​c.*99C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,603,650 control chromosomes in the GnomAD database, including 32,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6842 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25730 hom.)
• Consequence: HNF1B NM_000458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.447
• Publications: 19 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

ENSG00000277688 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-37687273-G-T is Benign according to our data. Variant chr17-37687273-G-T is described in ClinVar as Benign. ClinVar VariationId is 322941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	NM_000458.4	MANE Select	c.*99C>A		3_prime_UTR	Exon 9 of 9	NP_000449.1
	HNF1B	NM_001411100.1		c.*7C>A		3_prime_UTR	Exon 8 of 8	NP_001398029.1
	HNF1B	NM_001165923.4		c.*99C>A		3_prime_UTR	Exon 9 of 9	NP_001159395.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.*99C>A		3_prime_UTR	Exon 9 of 9	ENSP00000480291.1
	HNF1B	ENST00000621123.4	TSL:1	c.*99C>A		3_prime_UTR	Exon 9 of 9	ENSP00000482711.1
	HNF1B	ENST00000613727.4	TSL:1	c.*7C>A		3_prime_UTR	Exon 7 of 7	ENSP00000477524.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39916 AN: 151942 Hom.: 6817 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.258

GnomAD2 exomes AF: 0.190 AC: 47177 AN: 248192 AF XY: 0.188

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.179 AC: 259225 AN: 1451592 Hom.: 25730 Cov.: 30 AF XY: 0.180 AC XY: 129772 AN XY: 722564

African (AFR) AF: 0.511 AC: 17009 AN: 33282

American (AMR) AF: 0.132 AC: 5857 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 5894 AN: 26068

East Asian (EAS) AF: 0.121 AC: 4784 AN: 39604

South Asian (SAS) AF: 0.207 AC: 17808 AN: 85952

European-Finnish (FIN) AF: 0.148 AC: 7775 AN: 52666

Middle Eastern (MID) AF: 0.275 AC: 1580 AN: 5740

European-Non Finnish (NFE) AF: 0.169 AC: 186547 AN: 1103742

Other (OTH) AF: 0.199 AC: 11971 AN: 60034

GnomAD4 genome AF: 0.263 AC: 39998 AN: 152058 Hom.: 6842 Cov.: 32 AF XY: 0.260 AC XY: 19348 AN XY: 74324

African (AFR) AF: 0.495 AC: 20496 AN: 41408

American (AMR) AF: 0.183 AC: 2790 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 798 AN: 3470

East Asian (EAS) AF: 0.0987 AC: 511 AN: 5176

South Asian (SAS) AF: 0.188 AC: 910 AN: 4828

European-Finnish (FIN) AF: 0.152 AC: 1606 AN: 10590

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12026 AN: 67988

Other (OTH) AF: 0.260 AC: 549 AN: 2112

Alfa AF: 0.212 Hom.: 971

Bravo AF: 0.276

Asia WGS AF: 0.186 AC: 649 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Renal cysts and diabetes syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.8
DANN	Benign	0.82
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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: rs2229295; hg19: chr17-36047276;