rs760038979

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_175914.5(HNF4A):c.454G>A(p.Gly152Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:1O:1

Conservation

PhyloP100: 6.95

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_175914.5

BP4

Computational evidence support a benign effect (MetaRNN=0.30848426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5 linkuse as main transcript	c.454G>A	p.Gly152Ser	missense_variant	5/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.454G>A	p.Gly152Ser	missense_variant	5/10	1	NM_175914.5		P41235-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251446

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Aug 18, 2017

ACMG Criteria:PP3 (5 predictors), BP4 (6 predictors) -

Maturity onset diabetes mellitus in young

Other:1

Uncertain risk allele, 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 rs760038979 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Benign

0.96

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.31

T;T;T;T;T;T;T

MetaSVM

Benign

-0.43

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.55

N;.;N;.;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.28

T;.;T;.;T;T;T

Sift4G

Benign

0.85

T;T;T;T;T;T;T

Polyphen

0.0010, 0.023, 0.042, 0.017

.;B;B;.;B;B;.

Vest4

0.55

MutPred

0.35

.;.;.;.;Gain of methylation at K179 (P = 0.0492);Gain of methylation at K179 (P = 0.0492);Gain of methylation at K179 (P = 0.0492);

MVP

0.85

MPC

0.30

ClinPred

0.34

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over