chr12-120989027-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP6BS2

The NM_000545.8(HNF1A):​c.521C>T​(p.Ala174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A174A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

4
5
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.76

Publications

9 publications found
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 Gene-Disease associations (from GenCC):
  • monogenic diabetes
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • type 1 diabetes mellitus 20
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
  • diabetes mellitus, noninsulin-dependent
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • maturity-onset diabetes of the young type 3
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • hyperinsulinism due to HNF1A deficiency
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • maturity-onset diabetes of the young
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • nonpapillary renal cell carcinoma
    Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_000545.8
BP6
Variant 12-120989027-C-T is Benign according to our data. Variant chr12-120989027-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435429.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAd4 at 18 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF1ANM_000545.8 linkc.521C>T p.Ala174Val missense_variant Exon 2 of 10 ENST00000257555.11 NP_000536.6 P20823E0YMI7
HNF1ANM_001306179.2 linkc.521C>T p.Ala174Val missense_variant Exon 2 of 10 NP_001293108.2 P20823E0YMI7
HNF1ANM_001406915.1 linkc.521C>T p.Ala174Val missense_variant Exon 2 of 9 NP_001393844.1
HNF1AXM_024449168.2 linkc.521C>T p.Ala174Val missense_variant Exon 2 of 9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkc.521C>T p.Ala174Val missense_variant Exon 2 of 10 1 NM_000545.8 ENSP00000257555.5 A0A0A0MQU7

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152174
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000200
AC:
50
AN:
250584
AF XY:
0.000148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000694
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000836
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.0000691
AC:
101
AN:
1461788
Hom.:
0
Cov.:
33
AF XY:
0.0000660
AC XY:
48
AN XY:
727182
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.000715
AC:
32
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0000765
AC:
2
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86254
European-Finnish (FIN)
AF:
0.000787
AC:
42
AN:
53358
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000126
AC:
14
AN:
1111974
Other (OTH)
AF:
0.000166
AC:
10
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152292
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74470
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41562
American (AMR)
AF:
0.000457
AC:
7
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00104
AC:
11
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000118
Hom.:
0
Bravo
AF:
0.000125
ExAC
AF:
0.000123
AC:
15
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Apr 12, 2017
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 08, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: HNF1A c.521C>T (p.Ala174Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250584 control chromosomes in GnomAD. The observed variant frequency is approximately 8.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.521C>T has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young without strong evidence for causality (example: Bellann-Chantelot_2007, Furuzawa_2008, Colclough_2022, Bonnefond_2020). These reports do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18003757, 33046911, 34789499, 18672310, 33729509). Two clinical diagnostic laboratories have submitted clinical-significance assessments (likely benign and uncertain significance, respectively) for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1Benign:1
Dec 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

HNF1A: PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Uncertain
0.026
T
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
.;T;T;T;T;.
Eigen
Benign
0.13
Eigen_PC
Benign
0.20
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Uncertain
0.43
T;T;T;T;T;T
MetaSVM
Pathogenic
1.0
D
PhyloP100
1.8
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-1.6
N;.;.;.;N;N
REVEL
Pathogenic
0.65
Sift
Benign
0.22
T;.;.;.;T;T
Sift4G
Benign
0.28
T;T;T;T;T;T
Polyphen
0.81
.;.;.;.;.;P
Vest4
0.70
MVP
0.96
MPC
1.2
ClinPred
0.067
T
GERP RS
4.9
gMVP
0.96
Mutation Taster
=4/96
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs201934320; hg19: chr12-121426830; COSMIC: COSV57463543; API