20-44429456-C-G

Variant names:

• chr20-44429456-C-G
• rs3746575
• NM_175914.5:c.1217-67C>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.1217-67C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,595,626 control chromosomes in the GnomAD database, including 279,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24593 hom., cov: 28)
  • Exomes 𝑓: 0.59 (255323 hom.)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.378
• Publications: 13 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=-0.89).
• BP6: Variant 20-44429456-C-G is Benign according to our data. Variant chr20-44429456-C-G is described in ClinVar as Benign. ClinVar VariationId is 676886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.1217-67C>G		intron_variant	Intron 9 of 9	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.1217-67C>G		intron_variant	Intron 9 of 9	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes AF: 0.567 AC: 85607 AN: 151020 Hom.: 24597 Cov.: 28

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.717

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.584

GnomAD4 exome AF: 0.591 AC: 853730 AN: 1444488 Hom.: 255323 AF XY: 0.593 AC XY: 426397 AN XY: 719238

African (AFR) AF: 0.529 AC: 17520 AN: 33126

American (AMR) AF: 0.429 AC: 19133 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 18219 AN: 25970

East Asian (EAS) AF: 0.382 AC: 15095 AN: 39566

South Asian (SAS) AF: 0.602 AC: 51605 AN: 85772

European-Finnish (FIN) AF: 0.597 AC: 31792 AN: 53230

Middle Eastern (MID) AF: 0.678 AC: 3771 AN: 5564

European-Non Finnish (NFE) AF: 0.603 AC: 661551 AN: 1096890

Other (OTH) AF: 0.586 AC: 35044 AN: 59788

GnomAD4 genome AF: 0.567 AC: 85635 AN: 151138 Hom.: 24593 Cov.: 28 AF XY: 0.563 AC XY: 41530 AN XY: 73760

African (AFR) AF: 0.530 AC: 21800 AN: 41134

American (AMR) AF: 0.503 AC: 7640 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2444 AN: 3464

East Asian (EAS) AF: 0.353 AC: 1792 AN: 5078

South Asian (SAS) AF: 0.584 AC: 2806 AN: 4802

European-Finnish (FIN) AF: 0.578 AC: 5966 AN: 10316

Middle Eastern (MID) AF: 0.705 AC: 206 AN: 292

European-Non Finnish (NFE) AF: 0.607 AC: 41208 AN: 67860

Other (OTH) AF: 0.585 AC: 1221 AN: 2088

Alfa AF: 0.583 Hom.: 3276

Bravo AF: 0.558

Asia WGS AF: 0.471 AC: 1639 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Maturity onset diabetes mellitus in young Benign:1

-

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 rs3746575 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.48
DANN	Benign	0.60
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3746575; hg19: chr20-43058096; COSMIC: COSV57380799; COSMIC: COSV57380799;