12-75410538-T-A

Variant names:

• chr12-75410538-T-A
• rs954587676
• NM_001270396.2:c.339T>A

Variant summary

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

The NM_001270396.2(GLIPR1L2):​c.339T>A​(p.Phe113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GLIPR1L2 NM_001270396.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.611

Genes affected

GLIPR1L2 (HGNC:28592): (GLIPR1 like 2) This gene encodes a member of the cysteine-rich secretory protein, antigen 5, and pathogenesis-related 1 superfamily. Members of this family have roles in a variety of processes, including cancer and immune defense. This gene is located in a cluster with two related genes on chromosome 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIPR1L2	NM_001270396.2	c.339T>A	p.Phe113Leu	missense_variant	Exon 2 of 6	ENST00000550916.6	NP_001257325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIPR1L2	ENST00000550916.6	c.339T>A	p.Phe113Leu	missense_variant	Exon 2 of 6	1	NM_001270396.2	ENSP00000448248.1
GLIPR1L2	ENST00000320460.8	c.339T>A	p.Phe113Leu	missense_variant	Exon 2 of 4	1		ENSP00000317385.4
GLIPR1L2	ENST00000378692.7	c.18T>A	p.Phe6Leu	missense_variant	Exon 3 of 7	1		ENSP00000367963.3
GLIPR1L2	ENST00000547164.1	c.339T>A	p.Phe113Leu	missense_variant	Exon 2 of 3	5		ENSP00000447980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460392 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726504

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.339T>A (p.F113L) alteration is located in exon 2 (coding exon 2) of the GLIPR1L2 gene. This alteration results from a T to A substitution at nucleotide position 339, causing the phenylalanine (F) at amino acid position 113 to be replaced by a leucine (L). 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	Pathogenic	0.98
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.99	D;.;D;.
Vest4		0.75
MutPred		0.56		Gain of catalytic residue at Y114 (P = 0);.;Gain of catalytic residue at Y114 (P = 0);Gain of catalytic residue at Y114 (P = 0);
MVP		0.46
MPC		0.23
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.54
gMVP		0.73

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: rs954587676; hg19: chr12-75804318;