12-120996827-CTCAT-CTCATTCATTCAT

Variant names:

• chr12-120996827-C-CTCATTCAT
• rs58371019
• NM_000545.8:c.1309+94_1309+101dupTCATTCAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000545.8(HNF1A):​c.1309+94_1309+101dupTCATTCAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 1,530,040 control chromosomes in the GnomAD database, including 485,095 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42806 hom., cov: 0)
  • Exomes 𝑓: 0.80 (442289 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.434
• Publications: 8 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 -16 ACMG points.

• BP6: Variant 12-120996827-C-CTCATTCAT is Benign according to our data. Variant chr12-120996827-C-CTCATTCAT is described in ClinVar as Benign. ClinVar VariationId is 133355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.86 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.1309+94_1309+101dupTCATTCAT		intron	N/A	NP_000536.6
	HNF1A	NM_001306179.2		c.1309+94_1309+101dupTCATTCAT		intron	N/A	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.1309+94_1309+101dupTCATTCAT		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.1309+94_1309+101dupTCATTCAT		intron	N/A	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1309+94_1309+101dupTCATTCAT		intron	N/A	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000535955.5	TSL:1	n.43-655_43-648dupTCATTCAT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.741 AC: 111593 AN: 150678 Hom.: 42774 Cov.: 0

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.874

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.799

GnomAD2 exomes AF: 0.811 AC: 123997 AN: 152926 AF XY: 0.812

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.910

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.868

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.802

Gnomad OTH exome AF: 0.826

GnomAD4 exome AF: 0.799 AC: 1102298 AN: 1379242 Hom.: 442289 Cov.: 39 AF XY: 0.801 AC XY: 545657 AN XY: 681574

African (AFR) AF: 0.500 AC: 15854 AN: 31702

American (AMR) AF: 0.901 AC: 32200 AN: 35748

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 21631 AN: 24858

East Asian (EAS) AF: 0.882 AC: 31301 AN: 35504

South Asian (SAS) AF: 0.825 AC: 65060 AN: 78896

European-Finnish (FIN) AF: 0.799 AC: 38890 AN: 48646

Middle Eastern (MID) AF: 0.853 AC: 4774 AN: 5596

European-Non Finnish (NFE) AF: 0.798 AC: 846934 AN: 1060980

Other (OTH) AF: 0.797 AC: 45654 AN: 57312

GnomAD4 genome AF: 0.741 AC: 111674 AN: 150798 Hom.: 42806 Cov.: 0 AF XY: 0.744 AC XY: 54816 AN XY: 73630

African (AFR) AF: 0.524 AC: 21504 AN: 41064

American (AMR) AF: 0.873 AC: 13240 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 3013 AN: 3446

East Asian (EAS) AF: 0.867 AC: 4389 AN: 5060

South Asian (SAS) AF: 0.840 AC: 4000 AN: 4762

European-Finnish (FIN) AF: 0.808 AC: 8450 AN: 10454

Middle Eastern (MID) AF: 0.911 AC: 266 AN: 292

European-Non Finnish (NFE) AF: 0.806 AC: 54445 AN: 67558

Other (OTH) AF: 0.801 AC: 1677 AN: 2094

Alfa AF: 0.739 Hom.: 4223

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity-onset diabetes of the young type 3 (1)
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=181/19	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58371019; hg19: chr12-121434630; COSMIC: COSV57458941; COSMIC: COSV57458941;