12-120997547-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP5BP7

This summary comes from the ClinGen Evidence Repository: The c.1383C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 461 (p.(Pro461=)) of NM_000545.8. This variant was identified in a patient with an alternate molecular basis for disease (BP5; ClinVar: SCV000595127.1, personal communication from Genetic Services Laboratory, University of Chicago). Additionally, this synonymous variant is not predicted by SpliceAI to impact splicing (BP7). The variant frequency fell between the ClinGen MDEP BS1 and PM2_Supporting cutoffs; therefore, neither was applied. In summary, c.1383C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BP5, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6832031/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 synonymous

Scores

2

Clinical Significance

Likely benign reviewed by expert panel B:4

Conservation

PhyloP100: -7.30
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP5
For more information check the summary or visit ClinGen Evidence Repository.
BP7
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF1ANM_000545.8 linkc.1383C>T p.Pro461Pro synonymous_variant Exon 7 of 10 ENST00000257555.11 NP_000536.6 P20823E0YMI7
HNF1ANM_001306179.2 linkc.1383C>T p.Pro461Pro synonymous_variant Exon 7 of 10 NP_001293108.2 P20823E0YMI7
HNF1AXM_024449168.2 linkc.1383C>T p.Pro461Pro synonymous_variant Exon 7 of 9 XP_024304936.1
HNF1ANM_001406915.1 linkc.1309+805C>T intron_variant Intron 6 of 8 NP_001393844.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkc.1383C>T p.Pro461Pro synonymous_variant Exon 7 of 10 1 NM_000545.8 ENSP00000257555.5 A0A0A0MQU7

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249882
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135382
show subpopulations
Gnomad AFR exome
AF:
0.0000624
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461268
Hom.:
0
Cov.:
38
AF XY:
0.0000344
AC XY:
25
AN XY:
727000
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.0000378
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152288
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000416

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:2
-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

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 rs772756175 with MODY3. -

Jan 28, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not specified Benign:1
Jun 21, 2016
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Monogenic diabetes Benign:1
Apr 16, 2022
ClinGen Monogenic Diabetes Variant Curation Expert Panel
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation

The c.1383C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 461 (p.(Pro461=)) of NM_000545.8. This variant was identified in a patient with an alternate molecular basis for disease (BP5; ClinVar: SCV000595127.1, personal communication from Genetic Services Laboratory, University of Chicago). Additionally, this synonymous variant is not predicted by SpliceAI to impact splicing (BP7). The variant frequency fell between the ClinGen MDEP BS1 and PM2_Supporting cutoffs; therefore, neither was applied. In summary, c.1383C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BP5, BP7. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
CADD
Benign
1.7
DANN
Benign
0.88
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772756175; hg19: chr12-121435350; COSMIC: COSV57462250; COSMIC: COSV57462250; API