X-13776247-GAC-AAT

Variant names:

• chrX-13776247-GAC-AAT
• NM_001001995.3:c.826_828delGTCinsATT
• GPM6B p.Val276Ile

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001001995.3(GPM6B):​c.826_828delGTCinsATT​(p.Val276Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GPM6B NM_001001995.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.78
• 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]

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]

OFD1 Gene-Disease associations (from GenCC):

• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• OFD1-related ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• orofaciodigital syndrome I

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 23

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Simpson-Golabi-Behmel syndrome type 2

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.826_828delGTCinsATT	p.Val276Ile	missense	N/A	NP_001001995.1	Q13491-4
	GPM6B	NM_001001996.3		c.826_828delGTCinsATT	p.Val276Ile	missense	N/A	NP_001001996.1	Q13491-3
	GPM6B	NM_001318729.2		c.649_651delGTCinsATT	p.Val217Ile	missense	N/A	NP_001305658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPM6B	ENST00000316715.9	TSL:2 MANE Select	c.826_828delGTCinsATT	p.Val276Ile	missense	N/A	ENSP00000316861.4	Q13491-4
	GPM6B	ENST00000355135.6	TSL:1	c.826_828delGTCinsATT	p.Val276Ile	missense	N/A	ENSP00000347258.2	Q13491-3
	GPM6B	ENST00000356942.9	TSL:1	c.706_708delGTCinsATT	p.Val236Ile	missense	N/A	ENSP00000349420.5	Q13491-1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-13794366;