rs149647255

Positions:

chrX-13767190-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003611.3(OFD1):c.2663A>C(p.Lys888Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000758 in 1,209,088 control chromosomes in the GnomAD database, including 5 homozygotes. There are 223 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., 92 hem., cov: 23)

Exomes 𝑓: 0.00047 ( 2 hom. 131 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.361

Variant links:

Genes affected

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]

OFD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00684464).

BP6

Variant X-13767190-A-C is Benign according to our data. Variant chrX-13767190-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 159472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-13767190-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00354 (398/112373) while in subpopulation AFR AF= 0.0112 (346/30925). AF 95% confidence interval is 0.0102. There are 3 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OFD1	NM_003611.3 linkuse as main transcript	c.2663A>C	p.Lys888Thr	missense_variant	20/23	ENST00000340096.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OFD1	ENST00000340096.11 linkuse as main transcript	c.2663A>C	p.Lys888Thr	missense_variant	20/23	1	NM_003611.3	P1	O75665-1

Frequencies

GnomAD3 genomes

AF:

0.00356

AC:

400

AN:

112320

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

AN XY:

34478

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00318

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00728

GnomAD3 exomes

AF:

0.00116

AC:

212

AN:

183277

Hom.:

AF XY:

0.000723

AC XY:

AN XY:

67781

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.00102

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:

0.000135

Gnomad OTH exome

AF:

0.000884

GnomAD4 exome

AF:

0.000473

AC:

519

AN:

1096715

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

131

AN XY:

362099

show subpopulations

Gnomad4 AFR exome

AF:

0.0124

Gnomad4 AMR exome

AF:

0.00156

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000952

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.00354

AC:

398

AN:

112373

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

AN XY:

34541

show subpopulations

Gnomad4 AFR

AF:

0.0112

Gnomad4 AMR

AF:

0.00318

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:

0.00719

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.00489

ESP6500AA

AF:

0.0133

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00115

AC:

140

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 01, 2014

- -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Retinitis pigmentosa 23;C1510460:Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;.

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.65

T;T;T

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.2

N;D;N

REVEL

Benign

0.12

Sift

Uncertain

0.018

D;D;D

Sift4G

Benign

0.090

T;D;T

Polyphen

0.037

B;B;B

Vest4

0.22

MVP

0.84

MPC

0.40

ClinPred

0.019

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.084

gMVP

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over