rs149473481

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_003611.3(OFD1):c.2025G>T(p.Leu675Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,167,305 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. 7 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.13

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.110373855).

BP6

Variant X-13760485-G-T is Benign according to our data. Variant chrX-13760485-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 463453.

BS2

High Hemizygotes in GnomAdExome4 at 7 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3 link	c.2025G>T	p.Leu675Phe	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.2025G>T	p.Leu675Phe	missense_variant	Exon 16 of 23	1	NM_003611.3	ENSP00000344314.6		O75665-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111928

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:

0.00

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:

0.0000206

AC:

AN:

145754

AF XY:

0.0000414

show subpopulations

Gnomad AFR exome

AF:

0.0000811

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:

0.0000146

Gnomad OTH exome

AF:

0.000293

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1055377

Hom.:

Cov.:

AF XY:

0.0000205

AC XY:

AN XY:

341061

show subpopulations

African (AFR)

AF:

0.0000408

AC:

AN:

24496

American (AMR)

AF:

0.00

AC:

AN:

27705

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16397

East Asian (EAS)

AF:

0.00

AC:

AN:

29904

South Asian (SAS)

AF:

0.00

AC:

AN:

46735

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38728

Middle Eastern (MID)

AF:

0.000535

AC:

AN:

3740

European-Non Finnish (NFE)

AF:

0.0000219

AC:

AN:

823553

Other (OTH)

AF:

0.0000907

AC:

AN:

44119

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.0000179

AC:

AN:

111928

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34084

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30760

American (AMR)

AF:

0.00

AC:

AN:

10612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

2696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53195

Other (OTH)

AF:

0.00

AC:

AN:

1481

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.0000113

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L675F variant (also known as c.2025G>T), located in coding exon 16 of the OFD1 gene, results from a G to T substitution at nucleotide position 2025. The leucine at codon 675 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs149473481. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele was absent out of 2442 total male alleles studied. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Joubert syndrome;C1510460:Orofaciodigital syndrome I

Benign:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

CADD

Benign

1.3

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.;.

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Uncertain

0.025

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

-1.1

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.3

N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.071

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.71

P;B;P

Vest4

0.12

MutPred

0.12

Loss of ubiquitination at K680 (P = 0.1202);.;.;

MVP

0.85

MPC

0.15

ClinPred

0.047

GERP RS

-1.5

Varity_R

0.10

gMVP

0.10

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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