rs782473677

Variant names:

• chr22-19353365-C-A
• rs782473677
• NM_003325.4:c.2839G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-19353365-C-A
• chr22-19353365-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003325.4(HIRA):​c.2839G>T​(p.Val947Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V947I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HIRA NM_003325.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

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.2839G>T	p.Val947Leu	missense	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.2839G>T	p.Val947Leu	missense	Exon 23 of 25	ENSP00000263208.5	P54198-1
	HIRA	ENST00000340170.8	TSL:1	c.2218G>T	p.Val740Leu	missense	Exon 19 of 21	ENSP00000345350.4	P54198-2
	HIRA	ENST00000935861.1		c.2989G>T	p.Val997Leu	missense	Exon 23 of 25	ENSP00000605920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.44
Sift	Benign	0.36	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.88		Loss of methylation at R944 (P = 0.143)
MVP		0.62
MPC		1.1
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.54
gMVP		0.51
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs782473677; hg19: chr22-19340888;