Genetic Variant HNF1A:p.Gly288Gly (chr12-120994314-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_000545.8(HNF1A):c.864G>C(p.Gly288Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,605,008 control chromosomes in the GnomAD database, including 67,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G288G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 5699 hom., cov: 32)

Exomes 𝑓: 0.28 ( 62124 hom. )

Consequence

HNF1A
NM_000545.8 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: -0.278

Publications

53 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 12-120994314-G-C is Benign according to our data. Variant chr12-120994314-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129236.

BP7

Synonymous conserved (PhyloP=-0.278 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.359 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.864G>C	p.Gly288Gly	synonymous	Exon 4 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.864G>C	p.Gly288Gly	synonymous	Exon 4 of 10	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.864G>C	p.Gly288Gly	synonymous	Exon 4 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.864G>C	p.Gly288Gly	synonymous	Exon 4 of 10	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.864G>C	p.Gly288Gly	synonymous	Exon 4 of 10	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000538646.5	TSL:1	n.677G>C		non_coding_transcript_exon	Exon 3 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39771

AN:

151610

Hom.:

5688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.00348

Gnomad SAS

AF:

0.0998

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.283

GnomAD2 exomes

AF:

0.265

AC:

60579

AN:

228182

AF XY:

0.255

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.442

Gnomad ASJ exome

AF:

0.317

Gnomad EAS exome

AF:

0.00153

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.284

AC:

412146

AN:

1453280

Hom.:

62124

Cov.:

AF XY:

0.278

AC XY:

200498

AN XY:

722496

show subpopulations

African (AFR)

AF:

0.203

AC:

6772

AN:

33372

American (AMR)

AF:

0.425

AC:

18305

AN:

43028

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

8059

AN:

25840

East Asian (EAS)

AF:

0.00114

AC:

AN:

39592

South Asian (SAS)

AF:

0.103

AC:

8833

AN:

85550

European-Finnish (FIN)

AF:

0.275

AC:

14408

AN:

52480

Middle Eastern (MID)

AF:

0.241

AC:

1389

AN:

5756

European-Non Finnish (NFE)

AF:

0.305

AC:

338146

AN:

1107614

Other (OTH)

AF:

0.270

AC:

16189

AN:

60048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

17928

35857

53785

71714

89642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11016

22032

33048

44064

55080

<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:

0.262

AC:

39812

AN:

151728

Hom.:

5699

Cov.:

AF XY:

0.257

AC XY:

19025

AN XY:

74136

show subpopulations

African (AFR)

AF:

0.207

AC:

8538

AN:

41340

American (AMR)

AF:

0.367

AC:

5600

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

1079

AN:

3468

East Asian (EAS)

AF:

0.00349

AC:

AN:

5164

South Asian (SAS)

AF:

0.101

AC:

481

AN:

4784

European-Finnish (FIN)

AF:

0.266

AC:

2801

AN:

10548

Middle Eastern (MID)

AF:

0.283

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.301

AC:

20416

AN:

67860

Other (OTH)

AF:

0.279

AC:

588

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1411

2822

4232

5643

7054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.260

Hom.:

1733

Bravo

AF:

0.273

Asia WGS

AF:

0.0810

AC:

289

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Maturity-onset diabetes of the young type 3 (2)

Maturity onset diabetes mellitus in young (1)

Nonpapillary renal cell carcinoma (1)

not provided (1)

Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.9

(source)

DANN

Benign

0.90

PhyloP100

-0.28

Mutation Taster

=69/31

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over