chrX-68212097-T-G

Variant names:

• chrX-68212097-T-G
• rs375325266
• NM_002547.3:c.702+11A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002547.3(OPHN1):​c.702+11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,139,718 control chromosomes in the GnomAD database, including 3 homozygotes. There are 587 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 0.0012 (0 hom., 33 hem., cov: 23)
  • Exomes 𝑓: 0.0019 (3 hom. 554 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0500
• 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: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-68212097-T-G is Benign according to our data. Variant chrX-68212097-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159478.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00117 (131/111938) while in subpopulation AMR AF = 0.00218 (23/10547). AF 95% confidence interval is 0.00149. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 33 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	NM_002547.3	MANE Select	c.702+11A>C		intron	N/A	NP_002538.1
	OPHN1	NM_001437258.1		c.702+11A>C		intron	N/A	NP_001424187.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.702+11A>C		intron	N/A	ENSP00000347710.5
	OPHN1	ENST00000680503.1		n.1390A>C		non_coding_transcript_exon	Exon 8 of 8
	OPHN1	ENST00000681408.1		c.597+1765A>C		intron	N/A	ENSP00000506619.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 131 AN: 111938 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00130 AC: 213 AN: 163335 AF XY: 0.00112

Gnomad AFR exome AF: 0.000937

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00183

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000136

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00185 AC: 1902 AN: 1027780 Hom.: 3 Cov.: 20 AF XY: 0.00179 AC XY: 554 AN XY: 309376

African (AFR) AF: 0.000280 AC: 7 AN: 25030

American (AMR) AF: 0.00161 AC: 55 AN: 34247

Ashkenazi Jewish (ASJ) AF: 0.00192 AC: 36 AN: 18786

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29729

South Asian (SAS) AF: 0.000430 AC: 22 AN: 51109

European-Finnish (FIN) AF: 0.000100 AC: 4 AN: 40018

Middle Eastern (MID) AF: 0.00101 AC: 4 AN: 3965

European-Non Finnish (NFE) AF: 0.00215 AC: 1682 AN: 781110

Other (OTH) AF: 0.00208 AC: 91 AN: 43786

GnomAD4 genome AF: 0.00117 AC: 131 AN: 111938 Hom.: 0 Cov.: 23 AF XY: 0.000967 AC XY: 33 AN XY: 34128

African (AFR) AF: 0.000422 AC: 13 AN: 30783

American (AMR) AF: 0.00218 AC: 23 AN: 10547

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 6 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00 AC: 0 AN: 2704

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6083

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00166 AC: 88 AN: 53164

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00105 Hom.: 5

Bravo AF: 0.00139

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	X-linked intellectual disability-cerebellar hypoplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.56
PhyloP100		0.050
Mutation Taster		=100/0	polymorphism (auto)

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: rs375325266; hg19: chrX-67431939;