16-29993345-C-A

Variant names:

• chr16-29993345-C-A
• rs570816593
• NM_003609.5:c.1533G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003609.5(HIRIP3):​c.1533G>T​(p.Trp511Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,397,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HIRIP3 NM_003609.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.07
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003609.5. 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
	HIRIP3	NM_003609.5	MANE Select	c.1533G>T	p.Trp511Cys	missense	Exon 7 of 7	NP_003600.2
	HIRIP3	NM_001197323.1		c.*67G>T		3_prime_UTR	Exon 6 of 6	NP_001184252.1	Q9BW71-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIRIP3	ENST00000279392.8	TSL:1 MANE Select	c.1533G>T	p.Trp511Cys	missense	Exon 7 of 7	ENSP00000279392.3	Q9BW71-1
	HIRIP3	ENST00000948389.1		c.1539G>T	p.Trp513Cys	missense	Exon 7 of 7	ENSP00000618448.1
	HIRIP3	ENST00000918288.1		c.1524G>T	p.Trp508Cys	missense	Exon 7 of 7	ENSP00000588347.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000483 AC: 1 AN: 206948 AF XY: 0.00000910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397604 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 687406

African (AFR) AF: 0.00 AC: 0 AN: 31628

American (AMR) AF: 0.00 AC: 0 AN: 37202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39018

South Asian (SAS) AF: 0.00 AC: 0 AN: 77338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5426

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076552

Other (OTH) AF: 0.00 AC: 0 AN: 57450

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.78		Loss of MoRF binding (P = 0.0203)
MVP		0.77
MPC		0.53
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.34
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs570816593; hg19: chr16-30004666;