chr12-120996922-C-CA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000545.8(HNF1A):c.1309+184dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,506,614 control chromosomes in the GnomAD database, including 58 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0052 ( 18 hom., cov: 31)

Exomes 𝑓: 0.0044 ( 40 hom. )

Consequence

HNF1A
NM_000545.8 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: -0.992

Publications

3 publications found

Variant links:

COSMIC-nc: COSV99983166

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: Benign. The variant received -10 ACMG points.

BP6

Variant 12-120996922-C-CA is Benign according to our data. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-120996922-C-CA is described in CliVar as Benign. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00524 (797/151964) while in subpopulation NFE AF = 0.00494 (336/67992). AF 95% confidence interval is 0.00451. There are 18 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 797 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.1309+184dupA	intron_variant	Intron 6 of 9	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.1309+184dupA	intron_variant	Intron 6 of 9		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.1309+184dupA	intron_variant	Intron 6 of 8		NP_001393844.1
HNF1A	XM_024449168.2 link	c.1309+184dupA	intron_variant	Intron 6 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.1309+184dupA		intron_variant	Intron 6 of 9	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.00525

AC:

797

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0345

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00573

AC:

843

AN:

147196

AF XY:

0.00523

show subpopulations

Gnomad AFR exome

AF:

0.000441

Gnomad AMR exome

AF:

0.00216

Gnomad ASJ exome

AF:

0.00525

Gnomad EAS exome

AF:

0.0000917

Gnomad FIN exome

AF:

0.0334

Gnomad NFE exome

AF:

0.00393

Gnomad OTH exome

AF:

0.00351

GnomAD4 exome

AF:

0.00441

AC:

5968

AN:

1354650

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

2910

AN XY:

670342

show subpopulations

African (AFR)

AF:

0.000615

AC:

AN:

30882

American (AMR)

AF:

0.00200

AC:

AN:

35588

Ashkenazi Jewish (ASJ)

AF:

0.00539

AC:

134

AN:

24864

East Asian (EAS)

AF:

0.00

AC:

AN:

35382

South Asian (SAS)

AF:

0.0000645

AC:

AN:

77500

European-Finnish (FIN)

AF:

0.0309

AC:

1482

AN:

47962

Middle Eastern (MID)

AF:

0.000179

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.00394

AC:

4095

AN:

1040366

Other (OTH)

AF:

0.00285

AC:

161

AN:

56516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

292

584

876

1168

1460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00524

AC:

797

AN:

151964

Hom.:

Cov.:

AF XY:

0.00626

AC XY:

465

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

41420

American (AMR)

AF:

0.00282

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0345

AC:

363

AN:

10536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00494

AC:

336

AN:

67992

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00437

Hom.:

Bravo

AF:

0.00265

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs201039488 with MODY3. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.99

Mutation Taster

=198/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over