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rs193922586

chr12-120999464-G-Achr12-120999464-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The ENST00000544413.2(HNF1A):c.1626G>A(p.Glu542=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,888 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 3 hom., cov: 33)
Exomes 𝑓: 0.0013 ( 35 hom. )

Consequence

HNF1A
ENST00000544413.2 splice_region, synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -1.20
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-120999464-G-A is Benign according to our data. Variant chr12-120999464-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36807.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}. Variant chr12-120999464-G-A is described in Lovd as [Likely_benign]. Variant chr12-120999464-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.2 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00088 (134/152328) while in subpopulation SAS AF= 0.024 (116/4828). AF 95% confidence interval is 0.0205. There are 3 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 134 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HNF1ANM_000545.8 linkuse as main transcriptc.1624-19G>A intron_variant ENST00000257555.11
HNF1ANM_001306179.2 linkuse as main transcriptc.1626G>A p.Glu542= splice_region_variant, synonymous_variant 9/10
HNF1AXM_024449168.2 linkuse as main transcriptc.1698G>A p.Glu566= synonymous_variant 8/9
HNF1ANM_001406915.1 linkuse as main transcriptc.1432-19G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.1624-19G>A intron_variant 1 NM_000545.8 P4

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000880
AC:
134
AN:
152210
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.0240
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00248
AC:
621
AN:
250716
Hom.:
12
AF XY:
0.00348
AC XY:
472
AN XY:
135696
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000497
Gnomad EAS exome
AF:
0.000490
Gnomad SAS exome
AF:
0.0192
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00229
GnomAD4 exome
AF:
0.00130
AC:
1907
AN:
1461560
Hom.:
35
Cov.:
70
AF XY:
0.00187
AC XY:
1357
AN XY:
727094
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000459
Gnomad4 EAS exome
AF:
0.000252
Gnomad4 SAS exome
AF:
0.0197
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000567
Gnomad4 OTH exome
AF:
0.00195
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000880
AC:
134
AN:
152328
Hom.:
3
Cov.:
33
AF XY:
0.00122
AC XY:
91
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.0240
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000317
Hom.:
0
Bravo
AF:
0.000208
Asia WGS
AF:
0.0160
AC:
55
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 03, 2015This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 24, 2021- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Maturity-onset diabetes of the young type 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testing;curationWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2011- -
Maturity onset diabetes mellitus in young Benign:1
Benign, criteria provided, single submitterresearchClinical 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 rs193922586 with MODY3. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
Cadd
Benign
0.97
Dann
Benign
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs193922586; hg19: chr12-121437267; API