Genetic Variant HIRA:p.Pro885Pro (chr22-19354025-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4BP6_Very_StrongBP7BS2

The NM_003325.4(HIRA):c.2655G>A(p.Pro885Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,613,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

HIRA
NM_003325.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.35

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.241).

BP6

Variant 22-19354025-C-T is Benign according to our data. Variant chr22-19354025-C-T is described in ClinVar as Benign. ClinVar VariationId is 713436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.35 with no splicing effect.

BS2

High AC in GnomAd4 at 137 AD gene.

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.2655G>A	p.Pro885Pro	synonymous	Exon 22 of 25	NP_003316.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HIRA	ENST00000263208.5	TSL:1 MANE Select	c.2655G>A	p.Pro885Pro	synonymous	Exon 22 of 25	ENSP00000263208.5	P54198-1
HIRA	ENST00000340170.8	TSL:1	c.2034G>A	p.Pro678Pro	synonymous	Exon 18 of 21	ENSP00000345350.4	P54198-2
HIRA	ENST00000935861.1		c.2805G>A	p.Pro935Pro	synonymous	Exon 22 of 25	ENSP00000605920.1

Frequencies

GnomAD3 genomes

AF:

0.000900

AC:

137

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000530

AC:

132

AN:

249038

AF XY:

0.000423

show subpopulations

Gnomad AFR exome

AF:

0.00239

Gnomad AMR exome

AF:

0.000669

Gnomad ASJ exome

AF:

0.00490

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000309

AC:

452

AN:

1461026

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

222

AN XY:

726698

show subpopulations

African (AFR)

AF:

0.00302

AC:

101

AN:

33464

American (AMR)

AF:

0.000717

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00571

AC:

149

AN:

26080

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000465

AC:

AN:

85988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000108

AC:

120

AN:

1111716

Other (OTH)

AF:

0.000596

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000900

AC:

137

AN:

152294

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41562

American (AMR)

AF:

0.000916

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000800

Hom.:

Bravo

AF:

0.00102

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000534

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.6

(source)

DANN

Benign

0.94

PhyloP100

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over