chr12-120997671-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000535955.5(HNF1A):n.223C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000535 in 1,607,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

HNF1A
ENST00000535955.5 non_coding_transcript_exon

Scores

Splicing: ADA: 0.00004751

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -1.08

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014485568).

BP6

Variant 12-120997671-C-T is Benign according to our data. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420. Variant chr12-120997671-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 435420.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000302 (46/152342) while in subpopulation AFR AF = 0.00111 (46/41588). AF 95% confidence interval is 0.000852. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 46 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.1501+6C>T	splice_region_variant, intron_variant	Intron 7 of 9	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.1501+6C>T	splice_region_variant, intron_variant	Intron 7 of 9		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.1309+929C>T	intron_variant	Intron 6 of 8		NP_001393844.1
HNF1A	XM_024449168.2 link	c.1501+6C>T	splice_region_variant, intron_variant	Intron 7 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.1501+6C>T		splice_region_variant, intron_variant	Intron 7 of 9	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000934

AC:

AN:

235642

AF XY:

0.0000860

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000947

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000275

AC:

AN:

1455344

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

723582

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

43852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25960

East Asian (EAS)

AF:

0.00

AC:

AN:

39230

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109220

Other (OTH)

AF:

0.0000166

AC:

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000302

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000164

Hom.:

Bravo

AF:

0.000374

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Feb 09, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 27, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 rs374306837 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.0

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.26

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.54

M_CAP

Benign

0.043

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

PhyloP100

-1.1

Sift4G

Uncertain

0.035

Vest4

0.10

MVP

0.61

ClinPred

0.077

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000048

dbscSNV1_RF

Benign

0.022

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