chr20-44406131-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP7BP4

This summary comes from the ClinGen Evidence Repository: The c.123C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 41 (p.(Cys41=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.297, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.123C>T variant in gnomAD v2.1.1 is 0.00002295, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.123C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9870170/MONDO:0015967/085

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:5

Conservation

PhyloP100: -0.302

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.123C>T	p.Cys41Cys	synonymous_variant	Exon 2 of 10	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 link	c.123C>T	p.Cys41Cys	synonymous_variant	Exon 2 of 10	1	NM_175914.5	ENSP00000315180.4		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251114

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461424

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33472

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.0000383

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.0000504

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86236

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53258

Gnomad4 NFE exome

AF:

0.0000207

AC:

AN:

1111982

Gnomad4 Remaining exome

AF:

0.0000497

AC:

AN:

60370

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.00019253

AN:

0.00019253

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000146977

AN:

0.0000146977

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000203

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HNF4A: BP4, BP7 -

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely 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 rs147552575 in MODY, yet. -

Monogenic diabetes

Benign:1

Jan 12, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.123C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 41 (p.(Cys41=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.297, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.123C>T variant in gnomAD v2.1.1 is 0.00002295, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.123C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

Mutation Taster

=84/16

polymorphism

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

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