rs745975

Variant names:

• chr20-44406053-C-T
• rs745975
• NM_175914.5:c.50-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175914.5(HNF4A):​c.50-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,609,480 control chromosomes in the GnomAD database, including 40,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2830 hom., cov: 33)
  • Exomes 𝑓: 0.22 (38050 hom.)
• Consequence: HNF4A NM_175914.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001241
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.18
• Publications: 37 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-44406053-C-T is Benign according to our data. Variant chr20-44406053-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 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.50-5C>T		splice_region intron	N/A	NP_787110.2
	HNF4A	NM_000457.6		c.116-5C>T		splice_region intron	N/A	NP_000448.3
	HNF4A	NM_001258355.2		c.95-5C>T		splice_region intron	N/A	NP_001245284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.50-5C>T		splice_region intron	N/A	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.116-5C>T		splice_region intron	N/A	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.116-5C>T		splice_region intron	N/A	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27706 AN: 152172 Hom.: 2828 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.197 AC: 49450 AN: 250434 AF XY: 0.205

Gnomad AFR exome AF: 0.0978

Gnomad AMR exome AF: 0.0978

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.224 AC: 326643 AN: 1457190 Hom.: 38050 Cov.: 33 AF XY: 0.225 AC XY: 163452 AN XY: 725146

African (AFR) AF: 0.0951 AC: 3175 AN: 33396

American (AMR) AF: 0.103 AC: 4587 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 8093 AN: 26122

East Asian (EAS) AF: 0.181 AC: 7189 AN: 39688

South Asian (SAS) AF: 0.238 AC: 20496 AN: 86144

European-Finnish (FIN) AF: 0.194 AC: 10268 AN: 52982

Middle Eastern (MID) AF: 0.219 AC: 945 AN: 4308

European-Non Finnish (NFE) AF: 0.233 AC: 258317 AN: 1109682

Other (OTH) AF: 0.226 AC: 13573 AN: 60152

GnomAD4 genome AF: 0.182 AC: 27724 AN: 152290 Hom.: 2830 Cov.: 33 AF XY: 0.180 AC XY: 13384 AN XY: 74466

African (AFR) AF: 0.101 AC: 4200 AN: 41564

American (AMR) AF: 0.140 AC: 2147 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3470

East Asian (EAS) AF: 0.175 AC: 909 AN: 5184

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4824

European-Finnish (FIN) AF: 0.178 AC: 1889 AN: 10616

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15609 AN: 68008

Other (OTH) AF: 0.195 AC: 413 AN: 2114

Alfa AF: 0.216 Hom.: 5416

Bravo AF: 0.177

Asia WGS AF: 0.201 AC: 700 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.224

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Maturity-onset diabetes of the young (2)
-	-	1	Glycosuria (1)
-	-	1	Hyperinsulinism, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.24
DANN	Benign	0.85
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs745975; hg19: chr20-43034693; COSMIC: COSV57381263; COSMIC: COSV57381263;