rs199796094

Variant names:

• chr20-44406061-C-T
• rs199796094
• NM_175914.5:c.53C>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.53C>T​(p.Thr18Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,459,686 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 significance (★★). The gene HNF4A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.98
• Publications: 2 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

Specifications for HNF4A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.25139338).
• BS2: High AC in GnomAdExome4 at 28 AD gene.

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.53C>T	p.Thr18Met	missense	Exon 2 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.119C>T	p.Thr40Met	missense	Exon 2 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.98C>T	p.Thr33Met	missense	Exon 3 of 11	NP_001245284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.53C>T	p.Thr18Met	missense	Exon 2 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.119C>T	p.Thr40Met	missense	Exon 2 of 10	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.119C>T	p.Thr40Met	missense	Exon 2 of 10	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250880 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1459686 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 726214

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4402

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111764

Other (OTH) AF: 0.0000332 AC: 2 AN: 60224

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Maturity-onset diabetes of the young (1)
-	1	-	not provided (1)
-	1	-	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.031	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.0
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.017	D
Sift4G	Benign	0.13	T
Polyphen		0.93	P
Vest4		0.15
MutPred		0.18		Loss of phosphorylation at T40 (P = 0.0753)
MVP		0.66
MPC		0.22
ClinPred		0.19	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.46
Mutation Taster		=74/26	polymorphism

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: rs199796094; hg19: chr20-43034701;