X-13776244-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_001001995.3(GPM6B):c.831T>C(p.Ile277=) 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, single submitter B:1
• Conservation: PhyloP100: 0.242

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant X-13776244-A-G is Benign according to our data. Variant chrX-13776244-A-G is described in ClinVar as [Benign]. Clinvar id is 778977.Status of the report is criteria_provided_single_submitter, 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPM6B	NM_001001995.3	c.831T>C	p.Ile277=	synonymous_variant	7/8	ENST00000316715.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPM6B	ENST00000316715.9	c.831T>C	p.Ile277=	synonymous_variant	7/8	2	NM_001001995.3	P3

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2120 AN: 112047 Hom.: 47 Cov.: 24 AF XY: 0.0166 AC XY: 567 AN XY: 34209

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

GnomAD3 exomes AF: 0.00554 AC: 1013 AN: 182769 Hom.: 24 AF XY: 0.00345 AC XY: 232 AN XY: 67261

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 SAS 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

Gnomad4 AFR exome AF: 0.0686

Gnomad4 AMR exome AF: 0.00455

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000751

Gnomad4 OTH exome AF: 0.00655

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

Gnomad4 AFR AF: 0.0656

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00383 Hom.: 86

Bravo AF: 0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	13
Dann	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs36099093; hg19: chrX-13794363;