NM_175914.5:c.320-204C>G

Variant names:

• chr20-44413490-C-G
• rs13041396
• NM_175914.5:c.320-204C>G

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.320-204C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,006 control chromosomes in the GnomAD database, including 2,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.19 (2774 hom., cov: 31)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.387
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-44413490-C-G is Benign according to our data. Variant chr20-44413490-C-G is described in ClinVar as Benign. ClinVar VariationId is 676906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.199 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.320-204C>G		intron	N/A	NP_787110.2
	HNF4A	NM_000457.6		c.386-204C>G		intron	N/A	NP_000448.3
	HNF4A	NM_001258355.2		c.365-204C>G		intron	N/A	NP_001245284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.320-204C>G		intron	N/A	ENSP00000315180.4
	HNF4A	ENST00000316099.10	TSL:1	c.386-204C>G		intron	N/A	ENSP00000312987.3
	HNF4A	ENST00000415691.2	TSL:1	c.386-204C>G		intron	N/A	ENSP00000412111.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28280 AN: 151888 Hom.: 2775 Cov.: 31

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.198

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

GnomAD4 genome AF: 0.186 AC: 28283 AN: 152006 Hom.: 2774 Cov.: 31 AF XY: 0.181 AC XY: 13459 AN XY: 74312

African (AFR) AF: 0.199 AC: 8259 AN: 41452

American (AMR) AF: 0.205 AC: 3132 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 624 AN: 3470

East Asian (EAS) AF: 0.0139 AC: 72 AN: 5168

South Asian (SAS) AF: 0.121 AC: 584 AN: 4808

European-Finnish (FIN) AF: 0.118 AC: 1253 AN: 10574

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13735 AN: 67958

Other (OTH) AF: 0.196 AC: 414 AN: 2110

Alfa AF: 0.191 Hom.: 339

Bravo AF: 0.192

Asia WGS AF: 0.0810 AC: 284 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Maturity onset diabetes mellitus in young (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.63
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs13041396; hg19: chr20-43042130;