rs113308087

Variant names:

• chr20-44413767-T-C
• rs113308087
• NM_175914.5:c.393T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_175914.5(HNF4A):​c.393T>C​(p.Asn131Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,766 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (31 hom.)
• Consequence: HNF4A NM_175914.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -2.38
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 20-44413767-T-C is Benign according to our data. Variant chr20-44413767-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36351.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00595 (905/152208) while in subpopulation AFR AF = 0.0188 (782/41518). AF 95% confidence interval is 0.0177. There are 4 homozygotes in GnomAd4. There are 440 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 905 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.393T>C	p.Asn131Asn	synonymous	Exon 4 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.459T>C	p.Asn153Asn	synonymous	Exon 4 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.438T>C	p.Asn146Asn	synonymous	Exon 5 of 11	NP_001245284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.393T>C	p.Asn131Asn	synonymous	Exon 4 of 10	ENSP00000315180.4
	HNF4A	ENST00000316099.10	TSL:1	c.459T>C	p.Asn153Asn	synonymous	Exon 4 of 10	ENSP00000312987.3
	HNF4A	ENST00000415691.2	TSL:1	c.459T>C	p.Asn153Asn	synonymous	Exon 4 of 10	ENSP00000412111.1

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 895 AN: 152090 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00310

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00331 AC: 829 AN: 250482 AF XY: 0.00337

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00139 AC: 2036 AN: 1461558 Hom.: 31 Cov.: 32 AF XY: 0.00168 AC XY: 1221 AN XY: 727068

African (AFR) AF: 0.0196 AC: 657 AN: 33478

American (AMR) AF: 0.00125 AC: 56 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00166 AC: 66 AN: 39698

South Asian (SAS) AF: 0.0125 AC: 1074 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111838

Other (OTH) AF: 0.00267 AC: 161 AN: 60382

GnomAD4 genome AF: 0.00595 AC: 905 AN: 152208 Hom.: 4 Cov.: 32 AF XY: 0.00591 AC XY: 440 AN XY: 74420

African (AFR) AF: 0.0188 AC: 782 AN: 41518

American (AMR) AF: 0.00216 AC: 33 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00310 AC: 16 AN: 5154

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00573 Hom.: 5

Bravo AF: 0.00631

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Maturity-onset diabetes of the young type 1 (2)
-	-	1	Familial hyperinsulinism (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	1	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.028
DANN	Benign	0.45
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs113308087; hg19: chr20-43042407; COSMIC: COSV107335566;