NM_000458.4:c.1339+27T>C

Variant names:

• chr17-37704890-A-G
• rs2107133
• NM_000458.4:c.1339+27T>C

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.1339+27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,612,856 control chromosomes in the GnomAD database, including 12,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (724 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11357 hom.)
• Consequence: HNF1B NM_000458.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.629
• Publications: 9 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

LOC124903989 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-37704890-A-G is Benign according to our data. Variant chr17-37704890-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 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.1339+27T>C		intron	N/A	NP_000449.1
	HNF1B	NM_001411100.1		c.1339+27T>C		intron	N/A	NP_001398029.1
	HNF1B	NM_001165923.4		c.1261+27T>C		intron	N/A	NP_001159395.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.1339+27T>C		intron	N/A	ENSP00000480291.1
	HNF1B	ENST00000621123.4	TSL:1	c.1261+27T>C		intron	N/A	ENSP00000482711.1
	HNF1B	ENST00000613727.4	TSL:1	c.1261+27T>C		intron	N/A	ENSP00000477524.1

Frequencies

GnomAD3 genomes AF: 0.0872 AC: 13260 AN: 152080 Hom.: 724 Cov.: 32

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0697

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0727

Gnomad FIN AF: 0.0854

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.0975

GnomAD2 exomes AF: 0.0919 AC: 23102 AN: 251464 AF XY: 0.0965

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0813

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.119 AC: 173695 AN: 1460658 Hom.: 11357 Cov.: 32 AF XY: 0.119 AC XY: 86253 AN XY: 726728

African (AFR) AF: 0.0276 AC: 924 AN: 33476

American (AMR) AF: 0.0523 AC: 2341 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3847 AN: 26124

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39692

South Asian (SAS) AF: 0.0778 AC: 6713 AN: 86248

European-Finnish (FIN) AF: 0.0794 AC: 4238 AN: 53406

Middle Eastern (MID) AF: 0.114 AC: 659 AN: 5762

European-Non Finnish (NFE) AF: 0.133 AC: 148176 AN: 1110878

Other (OTH) AF: 0.112 AC: 6781 AN: 60350

GnomAD4 genome AF: 0.0871 AC: 13253 AN: 152198 Hom.: 724 Cov.: 32 AF XY: 0.0842 AC XY: 6263 AN XY: 74426

African (AFR) AF: 0.0302 AC: 1254 AN: 41520

American (AMR) AF: 0.0697 AC: 1066 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3468

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.0723 AC: 349 AN: 4824

European-Finnish (FIN) AF: 0.0854 AC: 905 AN: 10592

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8809 AN: 67996

Other (OTH) AF: 0.0960 AC: 203 AN: 2114

Alfa AF: 0.116 Hom.: 882

Bravo AF: 0.0829

Asia WGS AF: 0.0270 AC: 96 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.11
DANN	Benign	0.77
PhyloP100		-0.63
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: rs2107133; hg19: chr17-36064897;