chr20-44414310-A-C

Variant names:

• chr20-44414310-A-C
• rs11574739
• NM_175914.5:c.427-197A>C

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.427-197A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 152,168 control chromosomes in the GnomAD database, including 2,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.19 (2936 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.114
• Publications: 6 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=-0.91).
• BP6: Variant 20-44414310-A-C is Benign according to our data. Variant chr20-44414310-A-C is described in ClinVar as Benign. ClinVar VariationId is 676908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 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.427-197A>C		intron	N/A	NP_787110.2
	HNF4A	NM_000457.6		c.493-197A>C		intron	N/A	NP_000448.3
	HNF4A	NM_001258355.2		c.472-197A>C		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.427-197A>C		intron	N/A	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.493-197A>C		intron	N/A	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.493-197A>C		intron	N/A	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29087 AN: 152050 Hom.: 2936 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.191 AC: 29100 AN: 152168 Hom.: 2936 Cov.: 32 AF XY: 0.186 AC XY: 13845 AN XY: 74372

African (AFR) AF: 0.214 AC: 8874 AN: 41530

American (AMR) AF: 0.207 AC: 3171 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3472

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5178

South Asian (SAS) AF: 0.139 AC: 670 AN: 4816

European-Finnish (FIN) AF: 0.119 AC: 1256 AN: 10592

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13769 AN: 67970

Other (OTH) AF: 0.202 AC: 427 AN: 2116

Alfa AF: 0.197 Hom.: 1346

Bravo AF: 0.198

Asia WGS AF: 0.0930 AC: 325 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.9
DANN	Benign	0.53
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11574739; hg19: chr20-43042950;