20-44355726-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_175914.5(HNF4A):c.-79C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,308,684 control chromosomes in the GnomAD database, including 6 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 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 6 hom. )

Consequence

HNF4A
NM_175914.5 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.578

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]

HNF4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 20-44355726-C-T is Benign according to our data. Variant chr20-44355726-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1442643.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr20-44355726-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00021 (32/152376) while in subpopulation SAS AF = 0.00497 (24/4826). AF 95% confidence interval is 0.00343. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.-79C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HNF4A	ENST00000316673 link	c.-79C>T	5_prime_UTR_variant	Exon 1 of 10	1	NM_175914.5	ENSP00000315180.4	P41235-5
HNF4A	ENST00000457232.5 link	c.-79C>T	upstream_gene_variant		1		ENSP00000396216.1	P41235-6
HNF4A	ENST00000609795.5 link	c.-79C>T	upstream_gene_variant		1		ENSP00000476609.1	P41235-7
HNF4A	ENST00000609262.5 link	c.-310C>T	upstream_gene_variant		1		ENSP00000476310.1	B9VVT8

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152258

Hom.:

Cov.:

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:

0.00135

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000429

AC:

496

AN:

1156308

Hom.:

Cov.:

AF XY:

0.000560

AC XY:

330

AN XY:

589248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

27684

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

43692

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24148

Gnomad4 EAS exome

AF:

0.00231

AC:

AN:

38156

Gnomad4 SAS exome

AF:

0.00471

AC:

376

AN:

79784

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

50910

Gnomad4 NFE exome

AF:

0.00000119

AC:

AN:

837488

Gnomad4 Remaining exome

AF:

0.000620

AC:

AN:

49972

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.000210

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.0000653

AC:

0.0000653168

AN:

0.0000653168

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00135

AC:

0.00134979

AN:

0.00134979

Gnomad4 SAS

AF:

0.00497

AC:

0.00497306

AN:

0.00497306

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.000277

Hom.:

Bravo

AF:

0.0000756

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 07, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in two unrelated individuals in published literature with maturity onset diabetes of the young (MODY); however, the variant did not segregate completely with the condition in the family of one proband and familial segregation information was not provided for the other proband (PMID: 12242469, 21062274); In-silico analysis and one published study are inconclusive as to whether the variant alters gene function (PMID: 12242469). In the absence of additional RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 12242469, 23014256, 21062274) -

May 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with HNF4A-related conditions, however it has also been observed in unaffected controls (PMID: 12242469, 21062274). ClinVar contains an entry for this variant (Variation ID: 1442643). Studies have shown that this variant does not significantly alter or has an unclear effect on HNF4A gene expression (PMID: 12242469). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant occurs in a non-coding region of the HNF4A gene. It does not change the encoded amino acid sequence of the HNF4A protein. -

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

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.97

Mutation Taster

=300/0

polymorphism

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over