chr12-121001197-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000545.8(HNF1A):c.*5G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000387 in 1,613,844 control chromosomes in the GnomAD database, including 5 homozygotes. 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 0.0022 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

HNF1A
NM_000545.8 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.56

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:

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

C12orf43 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 12-121001197-G-A is Benign according to our data. Variant chr12-121001197-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377966.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00217 (330/152300) while in subpopulation AFR AF= 0.00755 (314/41574). AF 95% confidence interval is 0.00687. There are 4 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.*5G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
C12orf43	NM_022895.3 link	c.*2956C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000288757.7	NP_075046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.*5G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7
C12orf43	ENST00000288757 link	c.*2956C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_022895.3	ENSP00000288757.5		Q96C57

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

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:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000524

AC:

131

AN:

250210

Hom.:

AF XY:

0.000399

AC XY:

AN XY:

135452

show subpopulations

Gnomad AFR exome

AF:

0.00753

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1461544

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

125

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00711

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152300

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00755

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.00262

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2024	Variant summary: HNF1A c.5G>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.00052 in 250210 control chromosomes, predominantly at a frequency of 0.0075 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05). To our knowledge, no occurrence of c.5G>A in individuals affected with Maturity Onset Diabetes Of The Young 3 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 377966). Based on the evidence outlined above, the variant was classified as benign. -

Maturity onset diabetes mellitus in young

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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 rs112986697 with MODY3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2015	The c.*5G>A variant is located in the 3' untranslated region (3’ UTR) of the HNF1A gene. This variant results from a G to A substitution five bases downstream of the last translated codon. This variant was previously reported in the SNPDatabase as rs112986697. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.14% (3/2098) total alleles studied. The highest observed frequency was 0.86% (1/116) Mexican-American alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.28% (37/13006) total alleles studied, having been observed in 0.84% (37/4406) African American alleles. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over