12-120978765-A-G
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000545.8(HNF1A):c.-4A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,612,498 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 0.00019 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00038 ( 5 hom. )
Consequence
HNF1A
NM_000545.8 5_prime_UTR
NM_000545.8 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.61
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
Variant 12-120978765-A-G is Benign according to our data. Variant chr12-120978765-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447492.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Likely_risk_allele=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.-4A>G | 5_prime_UTR_variant | 1/10 | ENST00000257555.11 | NP_000536.6 | ||
HNF1A | NM_001306179.2 | c.-4A>G | 5_prime_UTR_variant | 1/10 | NP_001293108.2 | |||
HNF1A | NM_001406915.1 | c.-4A>G | 5_prime_UTR_variant | 1/9 | NP_001393844.1 | |||
HNF1A | XM_024449168.2 | c.-4A>G | 5_prime_UTR_variant | 1/9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
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HNF1A | ENST00000257555.11 | c.-4A>G | 5_prime_UTR_variant | 1/10 | 1 | NM_000545.8 | ENSP00000257555 | P4 | ||
HNF1A-AS1 | ENST00000619441.1 | n.128+1879T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 151980Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000829 AC: 203AN: 244814Hom.: 2 AF XY: 0.00107 AC XY: 143AN XY: 133948
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GnomAD4 exome AF: 0.000379 AC: 553AN: 1460400Hom.: 5 Cov.: 30 AF XY: 0.000535 AC XY: 389AN XY: 726542
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GnomAD4 genome AF: 0.000191 AC: 29AN: 152098Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 23AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Maturity onset diabetes mellitus in young Pathogenic:1Benign:1
Likely risk allele, flagged submission | 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. Sufficient evidence is found to confer the association of this particular variant rs561269721 with MODY3. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2017 | 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. - |
Maturity-onset diabetes of the young type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 02, 2017 | - - |
Nonpapillary renal cell carcinoma Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | HNF1A: BS1, BS2 - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at