rs773386088

Variant names:

• chr20-44419955-C-T
• rs773386088
• NM_175914.5:c.826+79C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-44419955-C-T
• chr20-44419955-C-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

This summary comes from the ClinGen Evidence Repository: The c.826+79C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within intron 7 of NM_175914.5 . The computational splicing predictor SpliceAI gives a score of 0.00 for donor loss, suggesting that the variant has no impact on splicing (BP4). This variant is not covered in gnomAD v2.1.1 exomes and has a Grpmax Filtering allele frequency of 0.000068 in gnomAD v3.1.2, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033)(BS1). In summary, c.826+79C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA315411486/MONDO:0015967/085

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: -0.950
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.826+79C>T		intron	N/A	NP_787110.2
	HNF4A	NM_000457.6		c.892+79C>T		intron	N/A	NP_000448.3
	HNF4A	NM_001258355.2		c.871+79C>T		intron	N/A	NP_001245284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.826+79C>T		intron	N/A	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.892+79C>T		intron	N/A	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.892+79C>T		intron	N/A	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000970 AC: 119 AN: 1226322 Hom.: 0 AF XY: 0.000101 AC XY: 63 AN XY: 621422

African (AFR) AF: 0.00 AC: 0 AN: 28920

American (AMR) AF: 0.00 AC: 0 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24624

East Asian (EAS) AF: 0.00 AC: 0 AN: 38584

South Asian (SAS) AF: 0.00 AC: 0 AN: 81210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52502

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5278

European-Non Finnish (NFE) AF: 0.000129 AC: 116 AN: 898132

Other (OTH) AF: 0.0000380 AC: 2 AN: 52660

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

African (AFR) AF: 0.0000483 AC: 2 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Monogenic diabetes (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.95
DANN	Benign	0.55
PhyloP100		-0.95

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: rs773386088; hg19: chr20-43048595;