12-2830804-C-A

Variant names:

• chr12-2830804-C-A
• rs1036210657
• NM_031474.3:c.399G>T

Variant summary

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

The NM_031474.3(NRIP2):​c.399G>T​(p.Gln133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NRIP2 NM_031474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.395

Genes affected

NRIP2 (HGNC:23078): (nuclear receptor interacting protein 2) Predicted to enable aspartic-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within Notch signaling pathway and negative regulation of transcription by RNA polymerase II. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ITFG2 (HGNC:30879): (integrin alpha FG-GAP repeat containing 2) Involved in cellular response to amino acid starvation; cellular response to glucose starvation; and negative regulation of TORC1 signaling. Located in lysosomal membrane. Part of KICSTOR complex. [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=0.113102764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRIP2	NM_031474.3	c.399G>T	p.Gln133His	missense_variant	Exon 2 of 6	ENST00000337508.9	NP_113662.1
ITFG2	NR_130744.3	n.2160C>A		non_coding_transcript_exon_variant	Exon 13 of 14
ITFG2	NR_147202.2	n.1475-30C>A		intron_variant	Intron 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRIP2	ENST00000337508.9	c.399G>T	p.Gln133His	missense_variant	Exon 2 of 6	1	NM_031474.3	ENSP00000337501.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727106

Gnomad4 AFR exome AF: 0.000179

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.399G>T (p.Q133H) alteration is located in exon 2 (coding exon 2) of the NRIP2 gene. This alteration results from a G to T substitution at nucleotide position 399, causing the glutamine (Q) at amino acid position 133 to be replaced by a histidine (H). 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	0.15
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.021	D;D;T
Sift4G	Benign	0.074	T;.;D
Polyphen		0.95	P;.;.
Vest4		0.39
MutPred		0.23		Gain of helix (P = 0.132);.;.;
MVP		0.16
MPC		0.15
ClinPred		0.53	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1036210657; hg19: chr12-2939970;