Variant 22-19353386-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_003325.4(HIRA):c.2818C>T(p.Leu940Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,986 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

HIRA
NM_003325.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.23

Variant links:

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 links:

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

C22orf39 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant where missense usually causes diseases, HIRA

BS2

High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIRA	NM_003325.4 linkuse as main transcript	c.2818C>T	p.Leu940Phe	missense_variant	23/25	ENST00000263208.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIRA	ENST00000263208.5 linkuse as main transcript	c.2818C>T	p.Leu940Phe	missense_variant	23/25	1	NM_003325.4	P1	P54198-1
HIRA	ENST00000340170.8 linkuse as main transcript	c.2197C>T	p.Leu733Phe	missense_variant	19/21	1			P54198-2
C22orf39	ENST00000509549.5 linkuse as main transcript	c.*2588C>T		3_prime_UTR_variant, NMD_transcript_variant	23/24	2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250866

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460692

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726646

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.000164

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.2818C>T (p.L940F) alteration is located in exon 23 (coding exon 23) of the HIRA gene. This alteration results from a C to T substitution at nucleotide position 2818, causing the leucine (L) at amino acid position 940 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Uncertain

0.030

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Uncertain

-0.096

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.089

T;D

Sift4G

Benign

0.14

T;T

Polyphen

0.97

D;D

Vest4

0.72

MutPred

0.61

.;Gain of methylation at R944 (P = 0.1562);

MVP

0.63

MPC

1.2

ClinPred

0.72

GERP RS

3.9

Varity_R

0.46

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over