12-120996827-CTCAT-CTCATTCATTCATTCAT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000545.8(HNF1A):c.1309+90_1309+101dupTCATTCATTCAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,530,548 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00076 ( 3 hom. )

Consequence

HNF1A
NM_000545.8 intron

Scores

Not classified

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.434

Publications

8 publications found

Variant links:

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)

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000504 (76/150894) while in subpopulation EAS AF = 0.00138 (7/5062). AF 95% confidence interval is 0.000648. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 76 AD,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.1309+90_1309+101dupTCATTCATTCAT	intron	N/A	NP_000536.6
HNF1A	NM_001306179.2		c.1309+90_1309+101dupTCATTCATTCAT	intron	N/A	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.1309+90_1309+101dupTCATTCATTCAT	intron	N/A	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1309+90_1309+101dupTCATTCATTCAT	intron	N/A	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.1309+90_1309+101dupTCATTCATTCAT	intron	N/A	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000535955.5	TSL:1	n.43-659_43-648dupTCATTCATTCAT	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000504

AC:

AN:

150776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00138

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000710

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000654

AC:

100

AN:

152926

AF XY:

0.000733

show subpopulations

Gnomad AFR exome

AF:

0.000118

Gnomad AMR exome

AF:

0.000455

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00226

Gnomad FIN exome

AF:

0.000197

Gnomad NFE exome

AF:

0.000802

Gnomad OTH exome

AF:

0.000457

GnomAD4 exome

AF:

0.000762

AC:

1051

AN:

1379654

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

527

AN XY:

681742

show subpopulations

African (AFR)

AF:

0.000221

AC:

AN:

31714

American (AMR)

AF:

0.000364

AC:

AN:

35754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24860

East Asian (EAS)

AF:

0.00282

AC:

100

AN:

35508

South Asian (SAS)

AF:

0.000634

AC:

AN:

78908

European-Finnish (FIN)

AF:

0.000103

AC:

AN:

48654

Middle Eastern (MID)

AF:

0.000893

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.000776

AC:

824

AN:

1061322

Other (OTH)

AF:

0.000820

AC:

AN:

57334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000504

AC:

AN:

150894

Hom.:

Cov.:

AF XY:

0.000489

AC XY:

AN XY:

73694

show subpopulations

African (AFR)

AF:

0.000268

AC:

AN:

41110

American (AMR)

AF:

0.000198

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00138

AC:

AN:

5062

South Asian (SAS)

AF:

0.00105

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000710

AC:

AN:

67586

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000139

Hom.:

4223

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.43

Mutation Taster

=92/8

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over