rs2259820

Variant names:

• chr12-120997539-C-T
• rs2259820
• NM_000545.8:c.1375C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000545.8(HNF1A):​c.1375C>T​(p.Leu459Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,612,850 control chromosomes in the GnomAD database, including 80,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L459L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6383 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74105 hom.)
• Consequence: HNF1A NM_000545.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.41
• Publications: 57 publications found

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

HNF1A Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 12-120997539-C-T is Benign according to our data. Variant chr12-120997539-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. 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
	HNF1A	NM_000545.8	MANE Select	c.1375C>T	p.Leu459Leu	synonymous	Exon 7 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1375C>T	p.Leu459Leu	synonymous	Exon 7 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.1309+797C>T		intron	N/A	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1375C>T	p.Leu459Leu	synonymous	Exon 7 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1375C>T	p.Leu459Leu	synonymous	Exon 7 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000535955.5	TSL:1	n.91C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41376 AN: 151942 Hom.: 6381 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.338 AC: 84358 AN: 249448 AF XY: 0.343

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.489

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.339

GnomAD4 exome AF: 0.312 AC: 456118 AN: 1460790 Hom.: 74105 Cov.: 41 AF XY: 0.316 AC XY: 229776 AN XY: 726740

African (AFR) AF: 0.118 AC: 3958 AN: 33478

American (AMR) AF: 0.373 AC: 16651 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 12253 AN: 26130

East Asian (EAS) AF: 0.523 AC: 20776 AN: 39688

South Asian (SAS) AF: 0.409 AC: 35295 AN: 86234

European-Finnish (FIN) AF: 0.309 AC: 16282 AN: 52760

Middle Eastern (MID) AF: 0.484 AC: 2787 AN: 5760

European-Non Finnish (NFE) AF: 0.295 AC: 328444 AN: 1111778

Other (OTH) AF: 0.326 AC: 19672 AN: 60342

GnomAD4 genome AF: 0.272 AC: 41378 AN: 152060 Hom.: 6383 Cov.: 32 AF XY: 0.279 AC XY: 20770 AN XY: 74326

African (AFR) AF: 0.126 AC: 5217 AN: 41528

American (AMR) AF: 0.346 AC: 5266 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1592 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2498 AN: 5140

South Asian (SAS) AF: 0.401 AC: 1932 AN: 4816

European-Finnish (FIN) AF: 0.321 AC: 3399 AN: 10578

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20343 AN: 67976

Other (OTH) AF: 0.312 AC: 659 AN: 2112

Alfa AF: 0.285 Hom.: 10515

Bravo AF: 0.267

Asia WGS AF: 0.418 AC: 1450 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Maturity-onset diabetes of the young type 3 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Maturity-onset diabetes of the young (2)
-	-	1	Nonpapillary renal cell carcinoma (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		3.4
Mutation Taster		=35/65	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: rs2259820; hg19: chr12-121435342; COSMIC: COSV57459043; COSMIC: COSV57459043;