22-19331389-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003325.4(HIRA):c.*51G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00911 in 1,610,926 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (262 hom.)
• Consequence: HIRA NM_003325.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.96

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]

LOC105372859 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-19331389-C-T is Benign according to our data. Variant chr22-19331389-C-T is described in ClinVar as [Benign]. Clinvar id is 1246924.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIRA	NM_003325.4	c.*51G>A		3_prime_UTR_variant	25/25	ENST00000263208.5
LOC105372859	XR_938002.3	n.667-165C>T		intron_variant, non_coding_transcript_variant
LOC105372859	XR_938000.3	n.561-165C>T		intron_variant, non_coding_transcript_variant
LOC105372859	XR_938001.3	n.561-165C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIRA	ENST00000263208.5	c.*51G>A		3_prime_UTR_variant	25/25	1	NM_003325.4	P1
HIRA	ENST00000340170.8	c.*51G>A		3_prime_UTR_variant	21/21	1

Frequencies

GnomAD3 genomes AF: 0.00760 AC: 1157 AN: 152180 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.0684

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0139 AC: 3451 AN: 247714 Hom.: 76 AF XY: 0.0151 AC XY: 2023 AN XY: 134194

Gnomad AFR exome AF: 0.000928

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.0700

Gnomad SAS exome AF: 0.0363

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.00927 AC: 13520 AN: 1458628 Hom.: 262 Cov.: 31 AF XY: 0.0101 AC XY: 7359 AN XY: 725678

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.0776

Gnomad4 SAS exome AF: 0.0366

Gnomad4 FIN exome AF: 0.000236

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.00761 AC: 1159 AN: 152298 Hom.: 27 Cov.: 33 AF XY: 0.00835 AC XY: 622 AN XY: 74474

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.0686

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00649 Hom.: 4

Bravo AF: 0.00678

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.063
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs117447448; hg19: chr22-19318912;