NM_003611.3:c.1399C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_003611.3(OFD1):c.1399C>T(p.Arg467Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,198,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000017 ( 0 hom. 7 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.288

Publications

3 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):

Joubert syndrome 10
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
OFD1-related ciliopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
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: Labcorp Genetics (formerly Invitae), G2P
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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10468325).

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003611.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OFD1	NM_003611.3	MANE Select	c.1399C>T	p.Arg467Cys	missense	Exon 13 of 23	NP_003602.1	O75665-1
OFD1	NM_001440947.1		c.1399C>T	p.Arg467Cys	missense	Exon 13 of 22	NP_001427876.1
OFD1	NM_001330209.2		c.1279C>T	p.Arg427Cys	missense	Exon 12 of 22	NP_001317138.1	O75665-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OFD1	ENST00000340096.11	TSL:1 MANE Select	c.1399C>T	p.Arg467Cys	missense	Exon 13 of 23	ENSP00000344314.6	O75665-1
OFD1	ENST00000380550.6	TSL:1	c.1279C>T	p.Arg427Cys	missense	Exon 12 of 22	ENSP00000369923.3	O75665-3
OFD1	ENST00000922714.1		c.1402C>T	p.Arg468Cys	missense	Exon 13 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes

AF:

0.0000981

AC:

AN:

112152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.000277

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183024

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000175

AC:

AN:

1086657

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

352615

show subpopulations

African (AFR)

AF:

0.0000764

AC:

AN:

26185

American (AMR)

AF:

0.00

AC:

AN:

35168

Ashkenazi Jewish (ASJ)

AF:

0.0000518

AC:

AN:

19306

East Asian (EAS)

AF:

0.00

AC:

AN:

30156

South Asian (SAS)

AF:

0.00

AC:

AN:

53833

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4109

European-Non Finnish (NFE)

AF:

0.0000168

AC:

AN:

831653

Other (OTH)

AF:

0.0000437

AC:

AN:

45721

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000981

AC:

AN:

112152

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34322

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30825

American (AMR)

AF:

0.00

AC:

AN:

10666

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2647

East Asian (EAS)

AF:

0.000277

AC:

AN:

3605

South Asian (SAS)

AF:

0.00

AC:

AN:

2723

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

53242

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.10

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.2

PhyloP100

0.29

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.27

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.054

MVP

0.87

MPC

0.17

ClinPred

0.41

GERP RS

0.99

Varity_R

0.17

gMVP

0.045

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over