12-120978765-A-G

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

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 2.61
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)

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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
HNF1ANM_000545.8 linkuse as main transcriptc.-4A>G 5_prime_UTR_variant 1/10 ENST00000257555.11 NP_000536.6
HNF1ANM_001306179.2 linkuse as main transcriptc.-4A>G 5_prime_UTR_variant 1/10 NP_001293108.2
HNF1ANM_001406915.1 linkuse as main transcriptc.-4A>G 5_prime_UTR_variant 1/9 NP_001393844.1
HNF1AXM_024449168.2 linkuse as main transcriptc.-4A>G 5_prime_UTR_variant 1/9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.-4A>G 5_prime_UTR_variant 1/101 NM_000545.8 ENSP00000257555 P4
HNF1A-AS1ENST00000619441.1 linkuse as main transcriptn.128+1879T>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
151980
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00580
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000829
AC:
203
AN:
244814
Hom.:
2
AF XY:
0.00107
AC XY:
143
AN XY:
133948
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00618
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000822
Gnomad OTH exome
AF:
0.000833
GnomAD4 exome
AF:
0.000379
AC:
553
AN:
1460400
Hom.:
5
Cov.:
30
AF XY:
0.000535
AC XY:
389
AN XY:
726542
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00546
Gnomad4 FIN exome
AF:
0.0000383
Gnomad4 NFE exome
AF:
0.0000423
Gnomad4 OTH exome
AF:
0.000481
GnomAD4 genome
AF:
0.000191
AC:
29
AN:
152098
Hom.:
0
Cov.:
31
AF XY:
0.000309
AC XY:
23
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00581
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000854
Hom.:
0
Bravo
AF:
0.0000907
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

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 submissionresearchClinical 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 submitterclinical testingAmbry GeneticsSep 18, 2017This 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingAthena DiagnosticsAug 02, 2017- -
Nonpapillary renal cell carcinoma Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2022HNF1A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.56
CADD
Benign
14
DANN
Benign
0.55

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: rs561269721; hg19: chr12-121416568; COSMIC: COSV57464693; API