16-19114835-G-A

Variant names:

• chr16-19114835-G-A
• rs1176161099
• NM_001034841.4:c.374G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001034841.4(ITPRIPL2):​c.374G>A​(p.Arg125Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ITPRIPL2 NM_001034841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

Genes affected

ITPRIPL2 (HGNC:27257): (ITPRIP like 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000261427 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10086915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPRIPL2	NM_001034841.4	c.374G>A	p.Arg125Gln	missense_variant	Exon 1 of 1	ENST00000381440.5	NP_001030013.1
ITPRIPL2	NR_028028.2	n.356G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPRIPL2	ENST00000381440.5	c.374G>A	p.Arg125Gln	missense_variant	Exon 1 of 1	6	NM_001034841.4	ENSP00000370849.3
ENSG00000261427	ENST00000564808.6	n.318G>A		non_coding_transcript_exon_variant	Exon 2 of 6	4
ITPRIPL2	ENST00000566735.1	n.388G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
ENSG00000261427	ENST00000568526.1	n.211+50G>A		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452782 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374G>A (p.R125Q) alteration is located in exon 1 (coding exon 1) of the ITPRIPL2 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a glutamine (Q). 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	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.46	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.059
Sift	Benign	0.38	T
Sift4G	Benign	0.24	T
Polyphen		0.66	P
Vest4		0.082
MutPred		0.41		Loss of MoRF binding (P = 0.0135);
MVP		0.14
ClinPred		0.57	D
GERP RS		3.1
Varity_R		0.036
gMVP		0.66

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

Other links and lift over

dbSNP: rs1176161099; hg19: chr16-19126157;