rs13041396

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.320-204C>G		intron_variant	Intron 3 of 9	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.320-204C>G		intron_variant	Intron 3 of 9	1	NM_175914.5	ENSP00000315180.4

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

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.196

Alfa AF: 0.191 Hom.: 339

Bravo AF: 0.192

Asia WGS AF: 0.0810 AC: 284 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Maturity onset diabetes mellitus in young Benign:1

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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs13041396 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs13041396; hg19: chr20-43042130;