dbSNP rs762555237: HNF1A:p.Pro300Pro (chr12-120994350-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000545.8(HNF1A):c.900C>T(p.Pro300Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,601,486 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene HNF1A is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

HNF1A
NM_000545.8 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -7.15

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_000545.8, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 12-120994350-C-T is Benign according to our data. Variant chr12-120994350-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000138 (200/1449300) while in subpopulation EAS AF = 0.00252 (99/39324). AF 95% confidence interval is 0.00212. There are 1 homozygotes in GnomAdExome4. There are 99 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 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.900C>T	p.Pro300Pro	synonymous	Exon 4 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.900C>T	p.Pro300Pro	synonymous	Exon 4 of 10	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.900C>T	p.Pro300Pro	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.900C>T	p.Pro300Pro	synonymous	Exon 4 of 10	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.900C>T	p.Pro300Pro	synonymous	Exon 4 of 10	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000538646.5	TSL:1	n.713C>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000187

AC:

AN:

224232

AF XY:

0.000115

show subpopulations

Gnomad AFR exome

AF:

0.0000735

Gnomad AMR exome

AF:

0.000160

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00172

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000698

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000138

AC:

200

AN:

1449300

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

719954

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33376

American (AMR)

AF:

0.000118

AC:

AN:

42324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25636

East Asian (EAS)

AF:

0.00252

AC:

AN:

39324

South Asian (SAS)

AF:

0.0000474

AC:

AN:

84400

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000813

AC:

AN:

1106470

Other (OTH)

AF:

0.0000167

AC:

AN:

59862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000460

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.00

Hom.:

Bravo

AF:

0.0000604

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Maturity-onset diabetes of the young (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.12

(source)

DANN

Benign

0.77

PhyloP100

-7.1

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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