Menu
GeneBe

rs1800574

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000545.8(HNF1A):c.293C>A(p.Ala98Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A98V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

HNF1A
NM_000545.8 missense

Scores

8
8
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.35
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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000545.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-120979061-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HNF1ANM_000545.8 linkuse as main transcriptc.293C>A p.Ala98Asp missense_variant 1/10 ENST00000257555.11
HNF1ANM_001306179.2 linkuse as main transcriptc.293C>A p.Ala98Asp missense_variant 1/10
HNF1ANM_001406915.1 linkuse as main transcriptc.293C>A p.Ala98Asp missense_variant 1/9
HNF1AXM_024449168.2 linkuse as main transcriptc.293C>A p.Ala98Asp missense_variant 1/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.293C>A p.Ala98Asp missense_variant 1/101 NM_000545.8 P4
HNF1A-AS1ENST00000619441.1 linkuse as main transcriptn.128+1583G>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
Cadd
Uncertain
25
Dann
Uncertain
1.0
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.0
D;.;.;.;D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;.;.;.;D;D
Sift4G
Uncertain
0.048
D;T;D;D;D;D
Polyphen
0.88
.;.;.;.;.;P
Vest4
0.76
MutPred
0.72
Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP
0.89
MPC
0.46
ClinPred
0.99
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
gMVP
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121416864; API