rs185831378

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_003611.3(OFD1):c.1930C>T(p.Arg644Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000795 in 1,207,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000080 ( 0 hom. 36 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.448

Publications

4 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057472587).

BP6

Variant X-13760390-C-T is Benign according to our data. Variant chrX-13760390-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000715 (8/111963) while in subpopulation EAS AF = 0.00168 (6/3561). AF 95% confidence interval is 0.000733. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 2 XL,AD,AR geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3 link	c.1930C>T	p.Arg644Cys	missense_variant	Exon 16 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.1930C>T	p.Arg644Cys	missense_variant	Exon 16 of 23	1	NM_003611.3	ENSP00000344314.6		O75665-1

Frequencies

GnomAD3 genomes

AF:

0.0000715

AC:

AN:

111911

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00168

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000243

AC:

AN:

181292

AF XY:

0.000273

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00282

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000370

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.0000803

AC:

AN:

1095245

Hom.:

Cov.:

AF XY:

0.0000997

AC XY:

AN XY:

361079

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26257

American (AMR)

AF:

0.00

AC:

AN:

34966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19241

East Asian (EAS)

AF:

0.00212

AC:

AN:

30164

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53857

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40491

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

840360

Other (OTH)

AF:

0.0000653

AC:

AN:

45933

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000715

AC:

AN:

111963

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34145

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30814

American (AMR)

AF:

0.00

AC:

AN:

10621

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00168

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2697

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53183

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.000162

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000272

AC:

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

Oct 12, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joubert syndrome;C1510460:Orofaciodigital syndrome I

Benign:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Jun 28, 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. -

not provided

Benign:1

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

9.5

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.21

T;.;.

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.82

T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

0.45

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Benign

0.17

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.055

B;B;B

Vest4

0.18

MVP

0.75

MPC

0.18

ClinPred

0.025

GERP RS

-1.5

Varity_R

0.12

gMVP

0.14

Mutation Taster

=96/4

polymorphism

(source)

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

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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