NM_001001995.3:c.458C>T

Variant names:

• chrX-13783432-G-A
• NM_001001995.3:c.458C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001001995.3(GPM6B):​c.458C>T​(p.Thr153Ile) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: GPM6B NM_001001995.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.47
• Publications: 0 publications found

Genes affected

GPM6B (HGNC:4461): (glycoprotein M6B) This gene encodes a membrane glycoprotein that belongs to the proteolipid protein family. Proteolipid protein family members are expressed in most brain regions and are thought to be involved in cellular housekeeping functions such as membrane trafficking and cell-to-cell communication. This protein may also be involved in osteoblast differentiation. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are located on chromosomes Y and 22. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001995.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPM6B	NM_001001995.3	MANE Select	c.458C>T	p.Thr153Ile	missense	Exon 4 of 8	NP_001001995.1	Q13491-4
	GPM6B	NM_001001996.3		c.458C>T	p.Thr153Ile	missense	Exon 4 of 8	NP_001001996.1	Q13491-3
	GPM6B	NM_001318729.2		c.281C>T	p.Thr94Ile	missense	Exon 3 of 7	NP_001305658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPM6B	ENST00000316715.9	TSL:2 MANE Select	c.458C>T	p.Thr153Ile	missense	Exon 4 of 8	ENSP00000316861.4	Q13491-4
	GPM6B	ENST00000355135.6	TSL:1	c.458C>T	p.Thr153Ile	missense	Exon 4 of 8	ENSP00000347258.2	Q13491-3
	GPM6B	ENST00000356942.9	TSL:1	c.338C>T	p.Thr113Ile	missense	Exon 3 of 7	ENSP00000349420.5	Q13491-1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.77		Loss of disorder (P = 0.037)
MVP		0.75
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		1.0
Mutation Taster		=6/94	disease causing

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

Other links and lift over

hg19: chrX-13801551;