rs555681479
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000545.8(HNF1A):c.901G>A(p.Ala301Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,600,064 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
HNF1A
NM_000545.8 missense
NM_000545.8 missense
Scores
2
5
10
Clinical Significance
Conservation
PhyloP100: 1.92
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 -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.23773482).
BS2
?
High AC in GnomAdExome4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.901G>A | p.Ala301Thr | missense_variant | 4/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.901G>A | p.Ala301Thr | missense_variant | 4/10 | ||
HNF1A | NM_001406915.1 | c.901G>A | p.Ala301Thr | missense_variant | 4/9 | ||
HNF1A | XM_024449168.2 | c.901G>A | p.Ala301Thr | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.901G>A | p.Ala301Thr | missense_variant | 4/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000451 AC: 10AN: 221838Hom.: 0 AF XY: 0.0000417 AC XY: 5AN XY: 119982
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GnomAD4 exome AF: 0.0000173 AC: 25AN: 1447908Hom.: 0 Cov.: 35 AF XY: 0.0000195 AC XY: 14AN XY: 719076
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 301 of the HNF1A protein (p.Ala301Thr). This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 10027593, 19336507). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function. ClinVar contains an entry for this variant (Variation ID: 586796). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 22, 2017 | - - |
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Madras Diabetes Research Foundation | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N
REVEL
Pathogenic
Sift
Benign
T;.;T;T
Sift4G
Benign
T;T;T;T
Polyphen
0.037
.;.;.;B
Vest4
MutPred
Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at