20-44355811-A-G

Variant names:

• chr20-44355811-A-G
• rs779464983
• NM_175914.5:c.7A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_175914.5(HNF4A):​c.7A>G​(p.Ser3Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2904867).

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.7A>G	p.Ser3Gly	missense	Exon 1 of 10	NP_787110.2
	HNF4A	NM_001030003.3		c.7A>G	p.Ser3Gly	missense	Exon 1 of 10	NP_001025174.1	P41235-6
	HNF4A	NM_001030004.3		c.7A>G	p.Ser3Gly	missense	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.7A>G	p.Ser3Gly	missense	Exon 1 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000457232.5	TSL:1	c.7A>G	p.Ser3Gly	missense	Exon 1 of 10	ENSP00000396216.1	P41235-6
	HNF4A	ENST00000609795.5	TSL:1	c.7A>G	p.Ser3Gly	missense	Exon 1 of 8	ENSP00000476609.1	P41235-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247386 AF XY: 0.00000743

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 FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461404 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.12
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.11	T
PhyloP100		5.5
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.49	T
Polyphen		0.12	B
Vest4		0.34
MutPred		0.19		Loss of glycosylation at S3 (P = 0.0643)
MVP		0.81
ClinPred		0.74	D
GERP RS		5.0
PromoterAI		0.055	Neutral
Mutation Taster		=78/22	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs779464983; hg19: chr20-42984451;