NM_175914.5:c.-83C>T

Variant names:

• chr20-44355722-C-T
• rs879092890
• NM_175914.5:c.-83C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_175914.5(HNF4A):​c.-83C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000699 in 1,259,794 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 Uncertain risk allele (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: HNF4A NM_175914.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:1 O:1
• Conservation: PhyloP100: 3.60
• Publications: 1 publications found

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]

R3HDML-AS1 (HGNC:55830): (R3HDML antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.-83C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	ENST00000316673.9	NP_787110.2
HNF4A	NM_175914.5	c.-83C>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	ENST00000316673.9	c.-83C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	1	NM_175914.5	ENSP00000315180.4
HNF4A	ENST00000316673.9	c.-83C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000686 AC: 76 AN: 1107558 Hom.: 0 Cov.: 15 AF XY: 0.0000688 AC XY: 39 AN XY: 566918

African (AFR) AF: 0.0000374 AC: 1 AN: 26720

American (AMR) AF: 0.000115 AC: 5 AN: 43374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23834

East Asian (EAS) AF: 0.00 AC: 0 AN: 37858

South Asian (SAS) AF: 0.00 AC: 0 AN: 78566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 0.0000844 AC: 67 AN: 793914

Other (OTH) AF: 0.0000619 AC: 3 AN: 48448

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Other:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain risk allele

Review Status: criteria provided, single submitter

Collection Method: research

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 rs879092890 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.95
PhyloP100		3.6
PromoterAI		-0.099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs879092890; hg19: chr20-42984362;