12-75410522-T-A

Variant names:

• chr12-75410522-T-A
• ENST00000378692.7:c.2T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The ENST00000378692.7(GLIPR1L2):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,192 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLIPR1L2 ENST00000378692.7 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.121

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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 13 codons. Genomic position: 75410557. Lost 0.052 part of the original CDS.
• 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.323T>A	p.Met108Lys	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	ENST00000378692.7	c.2T>A	p.Met1?	start_lost	Exon 3 of 7	1		ENSP00000367963.3
GLIPR1L2	ENST00000550916.6	c.323T>A	p.Met108Lys	missense_variant	Exon 2 of 6	1	NM_001270396.2	ENSP00000448248.1
GLIPR1L2	ENST00000320460.8	c.323T>A	p.Met108Lys	missense_variant	Exon 2 of 4	1		ENSP00000317385.4
GLIPR1L2	ENST00000547164.1	c.323T>A	p.Met108Lys	missense_variant	Exon 2 of 3	5		ENSP00000447980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460192 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726400

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: 9.00e-7

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

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323T>A (p.M108K) 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 323, causing the methionine (M) at amino acid position 108 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.4
DANN	Benign	0.90
DEOGEN2	Benign	0.0022	T;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.47	T;D;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.084	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.79	N;.;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.84	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.94	T;D;T;T
Sift4G	Benign	0.35	T;D;T;T
Polyphen		0.15	B;.;B;.
Vest4		0.43
MutPred		0.50		Gain of catalytic residue at F113 (P = 0.0019);.;Gain of catalytic residue at F113 (P = 0.0019);Gain of catalytic residue at F113 (P = 0.0019);
MVP		0.16
MPC		0.11
ClinPred		0.084	T
GERP RS		0.76
Varity_R		0.074
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-75804302;