20-44355806-T-C

Variant names:

• chr20-44355806-T-C
• rs1229650809
• NM_175914.5:c.2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PS4_Moderate PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.2T>C variant in the hepatic nuclear factor-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID:23348805). This variant is only present in one copy in the Latino/Admixed American subpopulation in gnomAD v2.1.1 and therefore a Popmax FAF is unavailable. Still, the variant meets the ClinGen MDEP threshold for PM2_Supporting (gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population) (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.2T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1_Strong, PS4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409109840/MONDO:0015967/085

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF4A NM_175914.5 start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:2 O:1
• Conservation: PhyloP100: 4.66
• Publications: 4 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]

R3HDML-AS1 (HGNC:55830): (R3HDML antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.2T>C	p.Met1?	start_lost	Exon 1 of 10	NP_787110.2
	HNF4A	NM_001030003.3		c.2T>C	p.Met1?	start_lost	Exon 1 of 10	NP_001025174.1	P41235-6
	HNF4A	NM_001030004.3		c.2T>C	p.Met1?	start_lost	Exon 1 of 8	NP_001025175.1	P41235-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000457232.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENSP00000396216.1	P41235-6
	HNF4A	ENST00000609795.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	ENSP00000476609.1	P41235-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247240 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461380 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
-	1	-	Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (1)
-	1	-	Maturity-onset diabetes of the young (1)
1	-	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.83	D
PhyloP100		4.7
PROVEAN	Benign	0.48	N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.074	T
Polyphen		0.81	P
Vest4		0.95
MutPred		0.98		Gain of glycosylation at M1 (P = 0.0041)
MVP		0.83
ClinPred		0.88	D
GERP RS		5.0
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=2/198	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1229650809; hg19: chr20-42984446;