rs145902391

Variant names:

• chr20-44424035-G-A
• rs145902391
• NM_175914.5:c.844G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-44424035-G-A
• chr20-44424035-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The c.844G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to asparagine at codon 282 (p.(Asp282Asn)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax minor filtering allele frequency of 0.000003000 (equal to the MDEP threshold of 0.000003), however, it has 3 copies in the European non-Finnish population (over the MDEP threshold of 2); therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant has a REVEL score of 0.42, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (PMID:27913849). In summary, c.844G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): no criteria met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9870393/MONDO:0015967/085

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 10.0
• 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]

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: Uncertain_significance. The variant received 0 ACMG points.

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.844G>A	p.Asp282Asn	missense	Exon 8 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.910G>A	p.Asp304Asn	missense	Exon 8 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.889G>A	p.Asp297Asn	missense	Exon 9 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.844G>A	p.Asp282Asn	missense	Exon 8 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.910G>A	p.Asp304Asn	missense	Exon 8 of 10	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.910G>A	p.Asp304Asn	missense	Exon 8 of 10	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247032 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460818 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726694

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

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

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Monogenic diabetes (2)
-	1	-	Maturity-onset diabetes of the young (1)
-	1	-	not specified (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	0.11
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.013
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.98	L
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.42
Sift	Benign	0.59	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.76
MVP		0.81
MPC		0.86
ClinPred		0.65	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.51
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145902391; hg19: chr20-43052675; COSMIC: COSV57383182;