chrX-13767190-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/20 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:6

Conservation

PhyloP100: -0.361

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 10
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
orofaciodigital syndrome I
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 23
Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome type 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Simpson-Golabi-Behmel syndrome type 2
Inheritance: XL Classification: LIMITED Submitted by: G2P

OFD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 159472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3 link	c.2663A>C	p.Lys888Thr	missense_variant	Exon 20 of 23	ENST00000340096.11	NP_003602.1	O75665-1E9KL37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11 link	c.2663A>C	p.Lys888Thr	missense_variant	Exon 20 of 23	1	NM_003611.3	ENSP00000344314.6		O75665-1

Frequencies

GnomAD3 genomes

AF:

0.00356

AC:

400

AN:

112320

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00116

AC:

212

AN:

183277

AF XY:

0.000723

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 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

African (AFR)

AF:

0.0124

AC:

326

AN:

26360

American (AMR)

AF:

0.00156

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40529

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.0000952

AC:

AN:

840768

Other (OTH)

AF:

0.00111

AC:

AN:

46045

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00354

AC:

398

AN:

112373

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

AN XY:

34541

show subpopulations

African (AFR)

AF:

0.0112

AC:

346

AN:

30925

American (AMR)

AF:

0.00318

AC:

AN:

10706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.00

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6168

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53236

Other (OTH)

AF:

0.00719

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 01, 2014

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome;C1510460:Orofaciodigital syndrome I

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Jan 10, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

Benign:1

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.

PhyloP100

-0.36

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over