rs137853831

chrX-129562453-C-AchrX-129562453-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5 BP4_Moderate BS2

The NM_000276.4(OCRL):c.1009C>A(p.Arg337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,096,160 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

Genes affected

OCRL (HGNC:8108): (OCRL inositol polyphosphate-5-phosphatase) This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-129562453-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68695.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11137441).
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.1009C>A	p.Arg337Ser	missense_variant	11/24	ENST00000371113.9
OCRL	NM_001318784.2	c.1012C>A	p.Arg338Ser	missense_variant	11/24
OCRL	NM_001587.4	c.1009C>A	p.Arg337Ser	missense_variant	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.1009C>A	p.Arg337Ser	missense_variant	11/24	1	NM_000276.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183438 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67886

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 SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 7 AN: 1096160 Hom.: 0 Cov.: 30 AF XY: 0.00000830 AC XY: 3 AN XY: 361614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Benign	0.91
DEOGEN2	Benign	0.38	T;.
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.15	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.88	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.0030	B;B
Vest4		0.093
MutPred		0.61		Gain of catalytic residue at R337 (P = 0.0264);Gain of catalytic residue at R337 (P = 0.0264);
MVP		0.92
MPC		1.3
ClinPred		0.10	T
GERP RS		4.7
Varity_R		0.45
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853831; hg19: chrX-128696430;