20-44414656-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_175914.5(HNF4A):​c.576C>T​(p.Asp192Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000505 in 1,604,478 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.932
Variant links:
Genes affected
HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 20-44414656-C-T is Benign according to our data. Variant chr20-44414656-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.932 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000191 (29/152212) while in subpopulation AFR AF= 0.000603 (25/41474). AF 95% confidence interval is 0.000419. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HNF4ANM_175914.5 linkc.576C>T p.Asp192Asp synonymous_variant 5/10 ENST00000316673.9 NP_787110.2 P41235-5F1D8T0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HNF4AENST00000316673.9 linkc.576C>T p.Asp192Asp synonymous_variant 5/101 NM_175914.5 ENSP00000315180.4 P41235-5

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000603
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000521
AC:
12
AN:
230148
Hom.:
0
AF XY:
0.0000484
AC XY:
6
AN XY:
124068
show subpopulations
Gnomad AFR exome
AF:
0.000415
Gnomad AMR exome
AF:
0.0000953
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:
0.0000291
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000358
AC:
52
AN:
1452266
Hom.:
0
Cov.:
33
AF XY:
0.0000388
AC XY:
28
AN XY:
721422
show subpopulations
Gnomad4 AFR exome
AF:
0.000689
Gnomad4 AMR exome
AF:
0.0000706
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000181
Gnomad4 OTH exome
AF:
0.0000832
GnomAD4 genome
AF:
0.000191
AC:
29
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.000603
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000494
Hom.:
0
Bravo
AF:
0.000246

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 05, 2024This 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. -
Benign, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs759574096 in MODY, yet. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 06, 2017- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 06, 2023- -
Type 2 diabetes mellitus;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 29, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Benign
0.25
DANN
Benign
0.55
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: rs759574096; hg19: chr20-43043296; COSMIC: COSV57383567; API