NM_175914.5:c.49+1224G>A

Variant names:

• chr20-44357077-G-A
• rs2144908
• NM_175914.5:c.49+1224G>A

Variant summary

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

The NM_175914.5(HNF4A):​c.49+1224G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,064 control chromosomes in the GnomAD database, including 3,529 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 0.19 (3529 hom., cov: 31)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• Publications: 54 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-AS1 (HGNC:49505): (HNF4A antisense RNA 1)

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 = 0.428 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.49+1224G>A		intron	N/A	NP_787110.2
	HNF4A	NM_001287183.2		c.-183+1224G>A		intron	N/A	NP_001274112.1
	HNF4A	NM_001030003.3		c.49+1224G>A		intron	N/A	NP_001025174.1	P41235-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.49+1224G>A		intron	N/A	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000457232.5	TSL:1	c.49+1224G>A		intron	N/A	ENSP00000396216.1	P41235-6
	HNF4A	ENST00000609795.5	TSL:1	c.49+1224G>A		intron	N/A	ENSP00000476609.1	P41235-7

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28867 AN: 151946 Hom.: 3511 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.210

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

GnomAD4 genome AF: 0.190 AC: 28913 AN: 152064 Hom.: 3529 Cov.: 31 AF XY: 0.199 AC XY: 14772 AN XY: 74298

African (AFR) AF: 0.104 AC: 4318 AN: 41506

American (AMR) AF: 0.374 AC: 5715 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 803 AN: 3472

East Asian (EAS) AF: 0.443 AC: 2283 AN: 5152

South Asian (SAS) AF: 0.297 AC: 1425 AN: 4806

European-Finnish (FIN) AF: 0.212 AC: 2239 AN: 10556

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11479 AN: 67990

Other (OTH) AF: 0.210 AC: 443 AN: 2110

Alfa AF: 0.183 Hom.: 8065

Bravo AF: 0.201

Asia WGS AF: 0.363 AC: 1259 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	3.0
DANN	Benign	0.65
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2144908; hg19: chr20-42985717;