16-29993667-C-A

Variant names:

• chr16-29993667-C-A
• rs368208784
• NM_003609.5:c.1381G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003609.5(HIRIP3):​c.1381G>T​(p.Ala461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,210 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HIRIP3 NM_003609.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.585
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1381G>T	p.Ala461Ser	missense	Exon 5 of 7	NP_003600.2
	HIRIP3	NM_001197323.1		c.443G>T	p.Gly148Val	missense	Exon 4 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.1381G>T	p.Ala461Ser	missense	Exon 5 of 7	ENSP00000279392.3	Q9BW71-1
	HIRIP3	ENST00000948389.1		c.1387G>T	p.Ala463Ser	missense	Exon 5 of 7	ENSP00000618448.1
	HIRIP3	ENST00000918288.1		c.1381G>T	p.Ala461Ser	missense	Exon 5 of 7	ENSP00000588347.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248518 AF XY: 0.0000149

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459358 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726102

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000672 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.0083	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.58
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.071
Sift	Benign	0.035	D
Sift4G	Uncertain	0.058	T
Polyphen		0.99	D
Vest4		0.33
MVP		0.46
MPC		0.18
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.099
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 2

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

Other links and lift over

dbSNP: rs368208784; hg19: chr16-30004988;