chrX-13776288-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001001995.3(GPM6B):​c.787C>T​(p.His263Tyr) variant causes a missense change. 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: 23)

Consequence

GPM6B
NM_001001995.3 missense

Scores

8
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.19
Variant links:
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]
OFD1 (HGNC:2567): (OFD1 centriole and centriolar satellite protein) This gene is located on the X chromosome and encodes a centrosomal protein. A knockout mouse model has been used to study the effect of mutations in this gene. The mouse gene is also located on the X chromosome, however, unlike the human gene it is not subject to X inactivation. Mutations in this gene are associated with oral-facial-digital syndrome type I and Simpson-Golabi-Behmel syndrome type 2. Many pseudogenes have been identified; a single pseudogene is found on chromosome 5 while as many as fifteen have been found on the Y chromosome. [provided by RefSeq, Aug 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPM6BNM_001001995.3 linkc.787C>T p.His263Tyr missense_variant Exon 7 of 8 ENST00000316715.9 NP_001001995.1 Q13491-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPM6BENST00000316715.9 linkc.787C>T p.His263Tyr missense_variant Exon 7 of 8 2 NM_001001995.3 ENSP00000316861.4 Q13491-4

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 08, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.787C>T (p.H263Y) alteration is located in exon 7 (coding exon 7) of the GPM6B gene. This alteration results from a C to T substitution at nucleotide position 787, causing the histidine (H) at amino acid position 263 to be replaced by a tyrosine (Y). 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
0.65
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
.;.;.;.;D;.
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D
MetaSVM
Uncertain
-0.065
T
MutationAssessor
Uncertain
2.7
.;.;.;.;M;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.7
D;D;D;D;D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0020
D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D
Polyphen
0.99, 1.0, 0.99
.;D;D;D;D;.
Vest4
0.71
MutPred
0.85
.;.;Loss of sheet (P = 0.1907);.;.;.;
MVP
0.78
MPC
0.91
ClinPred
0.96
D
GERP RS
5.8
Varity_R
0.87
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: chrX-13794407; COSMIC: COSV57422347; COSMIC: COSV57422347; API