rs1403350105

Variant names:

• chrX-68053653-T-C
• rs1403350105
• NM_002547.3:c.2316A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_002547.3(OPHN1):​c.2316A>G​(p.Thr772Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,689 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: OPHN1 NM_002547.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.340
• Publications: 0 publications found

Genes affected

OPHN1 (HGNC:8148): (oligophrenin 1) This gene encodes a Rho-GTPase-activating protein that promotes GTP hydrolysis of Rho subfamily members. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Mutations in this gene are responsible for OPHN1-related X-linked cognitive disability with cerebellar hypoplasia and distinctive facial dysmorhphism. [provided by RefSeq, Jul 2008]

OPHN1 Gene-Disease associations (from GenCC):

• X-linked intellectual disability-cerebellar hypoplasia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-68053653-T-C is Benign according to our data. Variant chrX-68053653-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 995148.
• BP7: Synonymous conserved (PhyloP=0.34 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002547.3. 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
	OPHN1	NM_002547.3	MANE Select	c.2316A>G	p.Thr772Thr	synonymous	Exon 22 of 25	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.1992A>G	p.Thr664Thr	synonymous	Exon 21 of 24	NP_001424187.1	A0A7P0Z4E9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.2316A>G	p.Thr772Thr	synonymous	Exon 22 of 25	ENSP00000347710.5	O60890-1
	OPHN1	ENST00000905069.1		c.2316A>G	p.Thr772Thr	synonymous	Exon 22 of 25	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.2211A>G	p.Thr737Thr	synonymous	Exon 21 of 24	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182039 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097689 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363075

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 54008

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841821

Other (OTH) AF: 0.00 AC: 0 AN: 46077

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.2
DANN	Benign	0.79
PhyloP100		0.34

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: rs1403350105; hg19: chrX-67273495;