rs117447448

Variant names:

• chr22-19331389-C-T
• rs117447448
• NM_003325.4:c.*51G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-19331389-C-T
• chr22-19331389-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.96
• Publications: 3 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]

HIRA Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

LOC105372859 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.015).
• BP6: Variant 22-19331389-C-T is Benign according to our data. Variant chr22-19331389-C-T is described in ClinVar as Benign. ClinVar VariationId is 1246924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

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.*51G>A		3_prime_UTR	Exon 25 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.*51G>A		3_prime_UTR	Exon 25 of 25	ENSP00000263208.5	P54198-1
	HIRA	ENST00000340170.8	TSL:1	c.*51G>A		3_prime_UTR	Exon 21 of 21	ENSP00000345350.4	P54198-2
	HIRA	ENST00000935861.1		c.*51G>A		3_prime_UTR	Exon 25 of 25	ENSP00000605920.1

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

GnomAD2 exomes AF: 0.0139 AC: 3451 AN: 247714 AF XY: 0.0151

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 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

African (AFR) AF: 0.00143 AC: 48 AN: 33458

American (AMR) AF: 0.00251 AC: 112 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 664 AN: 26118

East Asian (EAS) AF: 0.0776 AC: 3079 AN: 39668

South Asian (SAS) AF: 0.0366 AC: 3153 AN: 86176

European-Finnish (FIN) AF: 0.000236 AC: 12 AN: 50858

Middle Eastern (MID) AF: 0.0357 AC: 206 AN: 5766

European-Non Finnish (NFE) AF: 0.00492 AC: 5465 AN: 1111554

Other (OTH) AF: 0.0129 AC: 781 AN: 60342

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

African (AFR) AF: 0.000914 AC: 38 AN: 41572

American (AMR) AF: 0.00359 AC: 55 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3468

East Asian (EAS) AF: 0.0686 AC: 354 AN: 5162

South Asian (SAS) AF: 0.0439 AC: 212 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00522 AC: 355 AN: 68024

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00595 Hom.: 5

Bravo AF: 0.00678

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.063
DANN	Benign	0.42
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117447448; hg19: chr22-19318912;