rs36099093

Variant names:

• chrX-13776244-A-G
• rs36099093
• NM_001001995.3:c.831T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001001995.3(GPM6B):​c.831T>C​(p.Ile277Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,206,763 control chromosomes in the GnomAD database, including 107 homozygotes. There are 1,176 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (47 hom., 577 hem., cov: 24)
  • Exomes 𝑓: 0.0022 (60 hom. 599 hem.)
• Consequence: GPM6B NM_001001995.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.242
• 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: 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.033).
• BP6: Variant X-13776244-A-G is Benign according to our data. Variant chrX-13776244-A-G is described in ClinVar as Benign. ClinVar VariationId is 778977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.242 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

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.831T>C	p.Ile277Ile	synonymous	Exon 7 of 8	NP_001001995.1	Q13491-4
	GPM6B	NM_001001996.3		c.831T>C	p.Ile277Ile	synonymous	Exon 7 of 8	NP_001001996.1	Q13491-3
	GPM6B	NM_001318729.2		c.654T>C	p.Ile218Ile	synonymous	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.831T>C	p.Ile277Ile	synonymous	Exon 7 of 8	ENSP00000316861.4	Q13491-4
	GPM6B	ENST00000355135.6	TSL:1	c.831T>C	p.Ile277Ile	synonymous	Exon 7 of 8	ENSP00000347258.2	Q13491-3
	GPM6B	ENST00000356942.9	TSL:1	c.711T>C	p.Ile237Ile	synonymous	Exon 6 of 7	ENSP00000349420.5	Q13491-1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2120 AN: 112047 Hom.: 47 Cov.: 24

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00554 AC: 1013 AN: 182769 AF XY: 0.00345

Gnomad AFR exome AF: 0.0663

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.000268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00215 AC: 2354 AN: 1094663 Hom.: 60 Cov.: 27 AF XY: 0.00166 AC XY: 599 AN XY: 360199

African (AFR) AF: 0.0686 AC: 1805 AN: 26320

American (AMR) AF: 0.00455 AC: 160 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.0000371 AC: 2 AN: 53973

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00512 AC: 21 AN: 4105

European-Non Finnish (NFE) AF: 0.0000751 AC: 63 AN: 839041

Other (OTH) AF: 0.00655 AC: 301 AN: 45983

GnomAD4 genome AF: 0.0190 AC: 2128 AN: 112100 Hom.: 47 Cov.: 24 AF XY: 0.0168 AC XY: 577 AN XY: 34272

African (AFR) AF: 0.0656 AC: 2022 AN: 30812

American (AMR) AF: 0.00752 AC: 80 AN: 10633

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2675

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6152

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53184

Other (OTH) AF: 0.0118 AC: 18 AN: 1530

Alfa AF: 0.00745 Hom.: 285

Bravo AF: 0.0210

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		0.24
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36099093; hg19: chrX-13794363;