16-29994012-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003609.5(HIRIP3):c.1133C>T(p.Pro378Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,602,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

HIRIP3
NM_003609.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.945

Variant links:

Genes affected

HIRIP3 (HGNC:4917): (HIRA interacting protein 3) The HIRA protein shares sequence similarity with Hir1p and Hir2p, the two corepressors of histone gene transcription characterized in the yeast, Saccharomyces cerevisiae. The structural features of the HIRA protein suggest that it may function as part of a multiprotein complex. Several cDNAs encoding HIRA-interacting proteins, or HIRIPs, have been identified. In vitro, the protein encoded by this gene binds HIRA, as well as H2B and H3 core histones, indicating that a complex containing HIRA-HIRIP3 could function in some aspects of chromatin and histone metabolism. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[provided by RefSeq, Aug 2011]

HIRIP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0063758194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIRIP3	NM_003609.5 link	c.1133C>T	p.Pro378Leu	missense_variant	Exon 4 of 7	ENST00000279392.8	NP_003600.2	Q9BW71-1
HIRIP3	NM_001197323.1 link	c.302-204C>T		intron_variant	Intron 3 of 5		NP_001184252.1	Q9BW71-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HIRIP3	ENST00000279392.8 link	c.1133C>T	p.Pro378Leu	missense_variant	Exon 4 of 7	1	NM_003609.5	ENSP00000279392.3	Q9BW71-1
HIRIP3	ENST00000564026.1 link	c.302-204C>T		intron_variant	Intron 3 of 5	2		ENSP00000456824.1	Q9BW71-3
HIRIP3	ENST00000563053.1 link	n.1044-204C>T		intron_variant	Intron 3 of 5	2
HIRIP3	ENST00000563680.1 link	n.414-204C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000170

AC:

AN:

240870

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

129912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00413

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000276

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000835

AC:

121

AN:

1449948

Hom.:

Cov.:

AF XY:

0.0000777

AC XY:

AN XY:

720632

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00382

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000814

Gnomad4 OTH exome

AF:

0.000267

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1133C>T (p.P378L) alteration is located in exon 1 (coding exon 1) of the HIRIP3 gene. This alteration results from a C to T substitution at nucleotide position 1133, causing the proline (P) at amino acid position 378 to be replaced by a leucine (L). 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

0.072

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.1

DANN

Benign

0.42

DEOGEN2

Benign

0.0040

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.39

M_CAP

Benign

0.0036

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.8

REVEL

Benign

0.015

Sift

Benign

0.18

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.13

MVP

0.28

MPC

0.075

ClinPred

0.023

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.17

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