20-44355726-C-T

Variant names:

• chr20-44355726-C-T
• rs373143621
• NM_175914.5:c.-79C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.578

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]

ACMG classification

Verdict is Benign. Variant got -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: {Likely_benign=1, Uncertain_significance=2}. 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• 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	c.-79C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000316673.9	NP_787110.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152258 Hom.: 0 Cov.: 32

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.: 6 Cov.: 16 AF XY: 0.000560 AC XY: 330 AN XY: 589248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00231

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.000620

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152376 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74522

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

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. -

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) -

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	17
DANN	Benign	0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs373143621; hg19: chr20-42984366; COSMIC: COSV53837235; COSMIC: COSV53837235;