rs193922584
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_000545.8(HNF1A):c.1539C>T(p.Thr513=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00036 ( 0 hom. )
Consequence
HNF1A
NM_000545.8 synonymous
NM_000545.8 synonymous
Scores
9
Clinical Significance
Conservation
PhyloP100: -1.21
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 Likely_benign. Variant got -4 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
Variant 12-120999305-C-T is Benign according to our data. Variant chr12-120999305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36805.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=4, Uncertain_significance=1}. Variant chr12-120999305-C-T is described in Lovd as [Benign]. Variant chr12-120999305-C-T is described in Lovd as [Likely_benign].
BS2
?
High AC in GnomAd4 at 56 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1539C>T | p.Thr513= | synonymous_variant | 8/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.1539C>T | p.Thr513= | synonymous_variant | 8/10 | ||
HNF1A | NM_001406915.1 | c.1347C>T | p.Thr449= | synonymous_variant | 7/9 | ||
HNF1A | XM_024449168.2 | c.1539C>T | p.Thr513= | synonymous_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1539C>T | p.Thr513= | synonymous_variant | 8/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000361 AC: 55AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000518 AC: 130AN: 251184Hom.: 0 AF XY: 0.000508 AC XY: 69AN XY: 135866
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GnomAD4 exome AF: 0.000360 AC: 526AN: 1461722Hom.: 0 Cov.: 32 AF XY: 0.000353 AC XY: 257AN XY: 727170
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GnomAD4 genome ? AF: 0.000368 AC: 56AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | HNF1A: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2019 | This variant is associated with the following publications: (PMID: 27659712) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 22, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 29, 2020 | - - |
Maturity onset diabetes mellitus in young Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2016 | 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. - |
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 rs193922584 with MODY3. - |
Maturity-onset diabetes of the young type 3 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C2675866:Type 1 diabetes mellitus 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 12, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MutationTaster
Benign
D;D;D;D
Sift4G
Benign
T
Vest4
MVP
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 22
Find out detailed SpliceAI scores and Pangolin per-transcript scores at