12-75482074-A-G

Position:

• chr12-75482074-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006851.3(GLIPR1):​c.415A>G​(p.Thr139Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLIPR1 NM_006851.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

GLIPR1 (HGNC:17001): (GLI pathogenesis related 1) This gene encodes a protein with similarity to both the pathogenesis-related protein (PR) superfamily and the cysteine-rich secretory protein (CRISP) family. Increased expression of this gene is associated with myelomocytic differentiation in macrophage and decreased expression of this gene through gene methylation is associated with prostate cancer. The protein has proapoptotic activities in prostate and bladder cancer cells. This gene is a member of a cluster on chromosome 12 containing two other similar genes. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLIPR1	NM_006851.3	c.415A>G	p.Thr139Ala	missense_variant	2/6	ENST00000266659.8	NP_006842.2
GLIPR1	XM_047428131.1	c.415A>G	p.Thr139Ala	missense_variant	2/3		XP_047284087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLIPR1	ENST00000266659.8	c.415A>G	p.Thr139Ala	missense_variant	2/6	1	NM_006851.3	ENSP00000266659.3
GLIPR1	ENST00000456650.7	c.415A>G	p.Thr139Ala	missense_variant	2/6	1		ENSP00000391144.3
GLIPR1	ENST00000550491.1	c.63A>G	p.Thr21Thr	synonymous_variant	2/4	3		ENSP00000448008.1
GLIPR1	ENST00000536703.5	n.415A>G		non_coding_transcript_exon_variant	2/4	2		ENSP00000440595.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.415A>G (p.T139A) alteration is located in exon 2 (coding exon 2) of the GLIPR1 gene. This alteration results from a A to G substitution at nucleotide position 415, causing the threonine (T) at amino acid position 139 to be replaced by an alanine (A). 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	0.66
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.98	D;P
Vest4		0.93
MutPred		0.81		Gain of MoRF binding (P = 0.2613);Gain of MoRF binding (P = 0.2613);
MVP		0.65
MPC		0.63
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.85

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: rs774922818; hg19: chr12-75875854;