rs797045846

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_003611.3(OFD1):c.2584T>G(p.Ser862Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,204,287 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S862S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.192

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):

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=0.1190477).

BP6

Variant X-13763840-T-G is Benign according to our data. Variant chrX-13763840-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211787.

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.2584T>G	p.Ser862Ala	missense	Exon 19 of 23	NP_003602.1	O75665-1
OFD1	NM_001330209.2		c.2464T>G	p.Ser822Ala	missense	Exon 18 of 22	NP_001317138.1	O75665-3
OFD1	NM_001330210.2		c.2164T>G	p.Ser722Ala	missense	Exon 20 of 24	NP_001317139.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OFD1	ENST00000340096.11	TSL:1 MANE Select	c.2584T>G	p.Ser862Ala	missense	Exon 19 of 23	ENSP00000344314.6	O75665-1
OFD1	ENST00000380550.6	TSL:1	c.2464T>G	p.Ser822Ala	missense	Exon 18 of 22	ENSP00000369923.3	O75665-3
OFD1	ENST00000922714.1		c.2587T>G	p.Ser863Ala	missense	Exon 19 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes

AF:

0.0000625

AC:

AN:

111972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183226

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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:

0.00000549

AC:

AN:

1092315

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

357909

show subpopulations

African (AFR)

AF:

0.0000761

AC:

AN:

26290

American (AMR)

AF:

0.0000284

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19346

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.00

AC:

AN:

54029

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40431

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3921

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

837052

Other (OTH)

AF:

0.0000654

AC:

AN:

45853

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000625

AC:

AN:

111972

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34134

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30791

American (AMR)

AF:

0.000189

AC:

AN:

10590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3595

South Asian (SAS)

AF:

0.00

AC:

AN:

2683

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53167

Other (OTH)

AF:

0.00

AC:

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000208

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)

Primary ciliary dyskinesia (1)

Retinitis pigmentosa 23;C1510460:Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.43

CADD

Benign

7.7

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.35

M_CAP

Benign

0.068

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.3

PhyloP100

-0.19

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.33

Sift

Benign

0.13

Sift4G

Benign

0.53

Polyphen

0.99

Vest4

0.074

MutPred

0.13

Gain of helix (P = 0.0425)

MVP

0.89

MPC

0.12

ClinPred

0.082

GERP RS

-6.2

Varity_R

0.052

gMVP

0.060

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over