rs6103731

chr20-44418653-A-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.670+141A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 653,248 control chromosomes in the GnomAD database, including 102,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23129 hom., cov: 32)
  • Exomes 𝑓: 0.55 (79382 hom.)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.431

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=-0.88).
• BP6: Variant 20-44418653-A-G is Benign according to our data. Variant chr20-44418653-A-G is described in ClinVar as [Benign]. Clinvar id is 676879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.670+141A>G		intron_variant		ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.670+141A>G		intron_variant		1	NM_175914.5

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83173 AN: 151940 Hom.: 23120 Cov.: 32

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.572

GnomAD4 exome AF: 0.554 AC: 277904 AN: 501190 Hom.: 79382 AF XY: 0.552 AC XY: 146613 AN XY: 265428

Gnomad4 AFR exome AF: 0.524

Gnomad4 AMR exome AF: 0.442

Gnomad4 ASJ exome AF: 0.692

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.546

Gnomad4 NFE exome AF: 0.595

Gnomad4 OTH exome AF: 0.565

GnomAD4 genome AF: 0.547 AC: 83221 AN: 152058 Hom.: 23129 Cov.: 32 AF XY: 0.541 AC XY: 40217 AN XY: 74326

Gnomad4 AFR AF: 0.520

Gnomad4 AMR AF: 0.499

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.592

Gnomad4 OTH AF: 0.574

Alfa AF: 0.567 Hom.: 3834

Bravo AF: 0.544

Asia WGS AF: 0.404 AC: 1404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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 rs6103731 in MODY, yet. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.84
Dann	Benign	0.85

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: rs6103731; hg19: chr20-43047293; COSMIC: COSV57390557;