Genetic Variant HNF1A:p.Ala102Ala (chr12-120979074-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. BP4BP2BP7PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.306C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 102 (p.(Ala102=)) of NM_000545.8. This synonymous variant is not predicted by SpliceAI to impact splicing (BP4; BP7) and is at a nucleotide not predicted to be highly conserved (phyloP100way < 2). Additionally, has been observed in unknown phase with a pathogenic HNF1A variant (BP2; internal lab contributor). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, c.306C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BP2, BP4, BP7, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA482430491/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:6

Conservation

PhyloP100: -0.172

Publications

0 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 links:

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

HNF1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

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
HNF1A	NM_000545.8	MANE Select	c.306C>T	p.Ala102Ala	synonymous	Exon 1 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.306C>T	p.Ala102Ala	synonymous	Exon 1 of 10	NP_001293108.2
HNF1A	NM_001406915.1		c.306C>T	p.Ala102Ala	synonymous	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.306C>T	p.Ala102Ala	synonymous	Exon 1 of 10	ENSP00000257555.5
HNF1A	ENST00000544413.2	TSL:1	c.306C>T	p.Ala102Ala	synonymous	Exon 1 of 10	ENSP00000438804.1
HNF1A	ENST00000538646.5	TSL:1	n.306C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.00000420

AC:

AN:

237966

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000667

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1458486

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725204

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33434

American (AMR)

AF:

0.0000226

AC:

AN:

44334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85510

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110744

Other (OTH)

AF:

0.00

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00000656

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity onset diabetes mellitus in young

Benign:2

Oct 11, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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 rs1486966222 with MODY3.

not provided

Benign:2

Apr 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 12, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Nov 04, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Monogenic diabetes

Benign:1

Aug 13, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.306C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 102 (p.(Ala102=)) of NM_000545.8. This synonymous variant is not predicted by SpliceAI to impact splicing (BP4; BP7) and is at a nucleotide not predicted to be highly conserved (phyloP100way < 2). Additionally, has been observed in unknown phase with a pathogenic HNF1A variant (BP2; internal lab contributor). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, c.306C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BP2, BP4, BP7, PM2_Supporting.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

-0.17

PromoterAI

-0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=293/7

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over