2-96327580-A-C

Variant names:

• chr2-96327580-A-C
• rs2064124646
• NM_001008949.3:c.949A>C

Variant summary

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

The NM_001008949.3(ITPRIPL1):​c.949A>C​(p.Lys317Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ITPRIPL1 NM_001008949.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

Genes affected

ITPRIPL1 (HGNC:29371): (ITPRIP like 1) Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.11560163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPRIPL1	NM_001008949.3	c.949A>C	p.Lys317Gln	missense_variant	Exon 3 of 3	ENST00000439118.3	NP_001008949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPRIPL1	ENST00000439118.3	c.949A>C	p.Lys317Gln	missense_variant	Exon 3 of 3	1	NM_001008949.3	ENSP00000389308.2
ITPRIPL1	ENST00000420728.1	c.1042A>C	p.Lys348Gln	missense_variant	Exon 2 of 2	2		ENSP00000396552.1
ITPRIPL1	ENST00000361124.5	c.973A>C	p.Lys325Gln	missense_variant	Exon 1 of 1	6		ENSP00000355121.4
ITPRIPL1	ENST00000536814.1	c.925A>C	p.Lys309Gln	missense_variant	Exon 2 of 2	3		ENSP00000439566.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458626 Hom.: 0 Cov.: 35 AF XY: 0.00000689 AC XY: 5 AN XY: 725514

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.973A>C (p.K325Q) alteration is located in exon 1 (coding exon 1) of the ITPRIPL1 gene. This alteration results from a A to C substitution at nucleotide position 973, causing the lysine (K) at amino acid position 325 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	0.18
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.032	.;T;.
Eigen	Benign	-0.068
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.47, 0.61	.;P;P
Vest4		0.28
MutPred		0.48		.;Loss of methylation at K317 (P = 0.0071);.;
MVP		0.20
MPC		0.66
ClinPred		0.71	D
GERP RS		5.4
Varity_R		0.082
gMVP		0.70

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: rs2064124646; hg19: chr2-96993318;