NM_175914.5:c.319+2134C>T

Variant names:

• chr20-44409609-C-T
• rs6031587
• NM_175914.5:c.319+2134C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175914.5(HNF4A):​c.319+2134C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,226 control chromosomes in the GnomAD database, including 1,630 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1630 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 10 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]

HNF4A Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• hyperinsulinism due to HNF4A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.319+2134C>T		intron	N/A	NP_787110.2
	HNF4A	NM_000457.6		c.385+2134C>T		intron	N/A	NP_000448.3
	HNF4A	NM_001258355.2		c.364+2134C>T		intron	N/A	NP_001245284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.319+2134C>T		intron	N/A	ENSP00000315180.4
	HNF4A	ENST00000316099.10	TSL:1	c.385+2134C>T		intron	N/A	ENSP00000312987.3
	HNF4A	ENST00000415691.2	TSL:1	c.385+2134C>T		intron	N/A	ENSP00000412111.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15513 AN: 152110 Hom.: 1615 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0708

Gnomad OTH AF: 0.102

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.102 AC: 15557 AN: 152226 Hom.: 1630 Cov.: 32 AF XY: 0.107 AC XY: 7982 AN XY: 74446

African (AFR) AF: 0.0614 AC: 2550 AN: 41540

American (AMR) AF: 0.224 AC: 3423 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3466

East Asian (EAS) AF: 0.507 AC: 2625 AN: 5174

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4826

European-Finnish (FIN) AF: 0.0662 AC: 702 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0708 AC: 4816 AN: 68006

Other (OTH) AF: 0.103 AC: 217 AN: 2114

Alfa AF: 0.0846 Hom.: 1134

Bravo AF: 0.113

Asia WGS AF: 0.327 AC: 1136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.69
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6031587; hg19: chr20-43038249;