dbSNP rs193922584: HNF1A:p.Thr513Thr (chr12-120999305-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_000545.8(HNF1A):c.1539C>T(p.Thr513Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,614,038 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 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: -1.21

Publications

4 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 -8 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 12-120999305-C-T is Benign according to our data. Variant chr12-120999305-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36805.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00036 (526/1461722) while in subpopulation MID AF = 0.00243 (14/5768). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAdExome4. There are 257 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 56 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	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.1539C>T	p.Thr513Thr	synonymous	Exon 8 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.1539C>T	p.Thr513Thr	synonymous	Exon 8 of 10	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.1347C>T	p.Thr449Thr	synonymous	Exon 7 of 9	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1539C>T	p.Thr513Thr	synonymous	Exon 8 of 10	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.1539C>T	p.Thr513Thr	synonymous	Exon 8 of 10	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000540108.1	TSL:1	n.*979C>T		non_coding_transcript_exon	Exon 7 of 9	ENSP00000445445.1	P20823-8

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000518

AC:

130

AN:

251184

AF XY:

0.000508

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000617

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000360

AC:

526

AN:

1461722

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

257

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000626

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000325

AC:

361

AN:

1111996

Other (OTH)

AF:

0.000729

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

126

168

210

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:

0.000368

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41568

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000526

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00124

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Maturity-onset diabetes of the young (2)

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C2675866:Type 1 diabetes mellitus 20 (1)

Maturity-onset diabetes of the young type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.50

MetaRNN

Benign

0.022

PhyloP100

-1.2

Sift4G

Benign

0.069

Vest4

0.33

MVP

0.80

GERP RS

-9.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.55

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.55

Position offset: 22

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