rs368803937

Variant names:

• chrX-68073156-G-A
• rs368803937
• NM_002547.3:c.1830C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-68073156-G-A
• chrX-68073156-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_002547.3(OPHN1):​c.1830C>T​(p.Ser610Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000896 in 1,205,325 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes 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: 𝑓 0.000071 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000091 (0 hom. 35 hem.)
• Consequence: OPHN1 NM_002547.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.519
• 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: ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-68073156-G-A is Benign according to our data. Variant chrX-68073156-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211793.
• BP7: Synonymous conserved (PhyloP=0.519 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000915 (100/1093058) while in subpopulation EAS AF = 0.000133 (4/30102). AF 95% confidence interval is 0.0000458. There are 0 homozygotes in GnomAdExome4. There are 35 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 35 XL gene

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.1830C>T	p.Ser610Ser	synonymous	Exon 20 of 25	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.1830C>T	p.Ser610Ser	synonymous	Exon 20 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.1830C>T	p.Ser610Ser	synonymous	Exon 20 of 25	ENSP00000347710.5	O60890-1
	OPHN1	ENST00000905069.1		c.1830C>T	p.Ser610Ser	synonymous	Exon 20 of 25	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.1725C>T	p.Ser575Ser	synonymous	Exon 19 of 24	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes AF: 0.0000713 AC: 8 AN: 112267 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.000665

GnomAD2 exomes AF: 0.000195 AC: 33 AN: 169245 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000759

Gnomad ASJ exome AF: 0.00275

Gnomad EAS exome AF: 0.000382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.000473

GnomAD4 exome AF: 0.0000915 AC: 100 AN: 1093058 Hom.: 0 Cov.: 30 AF XY: 0.0000974 AC XY: 35 AN XY: 359184

African (AFR) AF: 0.0000760 AC: 2 AN: 26331

American (AMR) AF: 0.0000576 AC: 2 AN: 34738

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 40 AN: 19296

East Asian (EAS) AF: 0.000133 AC: 4 AN: 30102

South Asian (SAS) AF: 0.00 AC: 0 AN: 53099

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.0000596 AC: 50 AN: 839288

Other (OTH) AF: 0.0000436 AC: 2 AN: 45902

GnomAD4 genome AF: 0.0000713 AC: 8 AN: 112267 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34439

African (AFR) AF: 0.00 AC: 0 AN: 30938

American (AMR) AF: 0.00 AC: 0 AN: 10588

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2649

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53264

Other (OTH) AF: 0.000665 AC: 1 AN: 1504

Alfa AF: 0.000194 Hom.: 1

Bravo AF: 0.0000945

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.8
DANN	Benign	0.88
PhyloP100		0.52
Mutation Taster		=100/0	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: rs368803937; hg19: chrX-67292998;