20-44355529-G-T

Variant names:

• chr20-44355529-G-T
• rs148318607
• ENST00000735551.1:n.69C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The ENST00000735551.1(R3HDML-AS1):​n.69C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 152,306 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 Benign (★★).

• Frequency: Genomes: 𝑓 0.0039 (0 hom., cov: 32)
• Consequence: R3HDML-AS1 ENST00000735551.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10
• Publications: 1 publications found

Genes affected

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

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 20-44355529-G-T is Benign according to our data. Variant chr20-44355529-G-T is described in ClinVar as Benign. ClinVar VariationId is 435433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000735551.1. 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.-276G>T		upstream_gene	N/A	NP_787110.2
	HNF4A	NM_001287183.2		c.-507G>T		upstream_gene	N/A	NP_001274112.1
	HNF4A	NM_001030003.3		c.-276G>T		upstream_gene	N/A	NP_001025174.1	P41235-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	R3HDML-AS1	ENST00000735551.1		n.69C>A		non_coding_transcript_exon	Exon 1 of 5
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.-276G>T		upstream_gene	N/A	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000894460.1		c.-276G>T		upstream_gene	N/A	ENSP00000564519.1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74464

African (AFR) AF: 0.00565 AC: 235 AN: 41582

American (AMR) AF: 0.00536 AC: 82 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.0126 AC: 65 AN: 5174

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4820

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00359 Hom.: 0

Bravo AF: 0.00446

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.1
DANN	Benign	0.73
PhyloP100		1.1
PromoterAI		0.015	Neutral

Splicing

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

Other links and lift over

dbSNP: rs148318607; hg19: chr20-42984169;