22-19353500-G-T

Variant names:

• chr22-19353500-G-T
• rs782416995
• NM_003325.4:c.2704C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003325.4(HIRA):​c.2704C>A​(p.Arg902Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000274 in 1,457,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HIRA NM_003325.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• Publications: 0 publications found

Genes affected

HIRA (HGNC:4916): (histone cell cycle regulator) This gene encodes a histone chaperone that preferentially places the variant histone H3.3 in nucleosomes. Orthologs of this gene in yeast, flies, and plants are necessary for the formation of transcriptionally silent heterochomatin. This gene plays an important role in the formation of the senescence-associated heterochromatin foci. These foci likely mediate the irreversible cell cycle changes that occur in senescent cells. It is considered the primary candidate gene in some haploinsufficiency syndromes such as DiGeorge syndrome, and insufficient production of the gene may disrupt normal embryonic development. [provided by RefSeq, Jul 2008]

C22orf39 (HGNC:27012): (chromosome 22 open reading frame 39)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003325.4. 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
	HIRA	NM_003325.4	MANE Select	c.2704C>A	p.Arg902Arg	synonymous	Exon 23 of 25	NP_003316.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIRA	ENST00000263208.5	TSL:1 MANE Select	c.2704C>A	p.Arg902Arg	synonymous	Exon 23 of 25	ENSP00000263208.5	P54198-1
	HIRA	ENST00000340170.8	TSL:1	c.2083C>A	p.Arg695Arg	synonymous	Exon 19 of 21	ENSP00000345350.4	P54198-2
	HIRA	ENST00000935861.1		c.2854C>A	p.Arg952Arg	synonymous	Exon 23 of 25	ENSP00000605920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246708 AF XY: 0.0000150

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457822 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725032

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.0000224 AC: 1 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110748

Other (OTH) AF: 0.00 AC: 0 AN: 60164

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782416995; hg19: chr22-19341023;