chr22-19353405-G-A

Position:

• chr22-19353405-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003325.4(HIRA):​c.2799C>T​(p.His933=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,102 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (20 hom.)
• Consequence: HIRA NM_003325.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.52

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 22-19353405-G-A is Benign according to our data. Variant chr22-19353405-G-A is described in ClinVar as [Benign]. Clinvar id is 714835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00781 (1189/152306) while in subpopulation AFR AF= 0.0247 (1027/41554). AF 95% confidence interval is 0.0235. There are 14 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIRA	NM_003325.4	c.2799C>T	p.His933=	synonymous_variant	23/25	ENST00000263208.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIRA	ENST00000263208.5	c.2799C>T	p.His933=	synonymous_variant	23/25	1	NM_003325.4	P1
HIRA	ENST00000340170.8	c.2178C>T	p.His726=	synonymous_variant	19/21	1
C22orf39	ENST00000509549.5	c.*2569C>T		3_prime_UTR_variant, NMD_transcript_variant	23/24	2

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1189 AN: 152188 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00319 AC: 799 AN: 250166 Hom.: 14 AF XY: 0.00244 AC XY: 331 AN XY: 135428

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000593

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00142 AC: 2073 AN: 1460796 Hom.: 20 Cov.: 32 AF XY: 0.00126 AC XY: 916 AN XY: 726692

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000468

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00781 AC: 1189 AN: 152306 Hom.: 14 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74472

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00487 Hom.: 5

Bravo AF: 0.00898

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

HIRA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.0
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34000365; hg19: chr22-19340928;