NM_001001995.3:c.826G>A

Variant names:

• chrX-13776249-C-T
• rs757587714
• NM_001001995.3:c.826G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001001995.3(GPM6B):​c.826G>A​(p.Val276Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000655 in 1,206,252 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000052 (0 hom. 11 hem.)
• Consequence: GPM6B NM_001001995.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17223889).
• BS2: High Hemizygotes in GnomAd4 at 3 gene

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.826G>A	p.Val276Ile	missense	Exon 7 of 8	NP_001001995.1	Q13491-4
	GPM6B	NM_001001996.3		c.826G>A	p.Val276Ile	missense	Exon 7 of 8	NP_001001996.1	Q13491-3
	GPM6B	NM_001318729.2		c.649G>A	p.Val217Ile	missense	Exon 6 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.826G>A	p.Val276Ile	missense	Exon 7 of 8	ENSP00000316861.4	Q13491-4
	GPM6B	ENST00000355135.6	TSL:1	c.826G>A	p.Val276Ile	missense	Exon 7 of 8	ENSP00000347258.2	Q13491-3
	GPM6B	ENST00000356942.9	TSL:1	c.706G>A	p.Val236Ile	missense	Exon 6 of 7	ENSP00000349420.5	Q13491-1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 22 AN: 111856 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000753

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000657 AC: 12 AN: 182692 AF XY: 0.0000298

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000521 AC: 57 AN: 1094343 Hom.: 0 Cov.: 27 AF XY: 0.0000306 AC XY: 11 AN XY: 359887

African (AFR) AF: 0.000114 AC: 3 AN: 26316

American (AMR) AF: 0.000341 AC: 12 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19337

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 53893

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.0000477 AC: 40 AN: 838875

Other (OTH) AF: 0.0000435 AC: 2 AN: 45955

GnomAD4 genome AF: 0.000197 AC: 22 AN: 111909 Hom.: 0 Cov.: 23 AF XY: 0.0000880 AC XY: 3 AN XY: 34109

African (AFR) AF: 0.000519 AC: 16 AN: 30809

American (AMR) AF: 0.000188 AC: 2 AN: 10617

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000753 AC: 4 AN: 53132

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.000143 Hom.: 1

Bravo AF: 0.000136

ExAC AF: 0.0000824 AC: 10

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	Benign	0.16
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.17	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.11	N
REVEL	Uncertain	0.64
Sift	Benign	0.25	T
Sift4G	Uncertain	0.016	D
Polyphen		0.97	D
Vest4		0.42
MVP		0.54
MPC		1.4
ClinPred		0.074	T
GERP RS		5.5
Varity_R		0.18
gMVP		0.88
Mutation Taster		=95/5	polymorphism

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

dbSNP: rs757587714; hg19: chrX-13794368; COSMIC: COSV104414362; COSMIC: COSV104414362;