X-13760490-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003611.3(OFD1):c.2030A>T(p.Glu677Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,166,428 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.459

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.2030A>T	p.Glu677Val	missense	Exon 16 of 23	NP_003602.1	O75665-1
OFD1	NM_001440947.1		c.2030A>T	p.Glu677Val	missense	Exon 16 of 22	NP_001427876.1
OFD1	NM_001330209.2		c.1910A>T	p.Glu637Val	missense	Exon 15 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.2030A>T	p.Glu677Val	missense	Exon 16 of 23	ENSP00000344314.6	O75665-1
OFD1	ENST00000380550.6	TSL:1	c.1910A>T	p.Glu637Val	missense	Exon 15 of 22	ENSP00000369923.3	O75665-3
OFD1	ENST00000922714.1		c.2033A>T	p.Glu678Val	missense	Exon 16 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000975

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000690

AC:

AN:

144889

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000190

AC:

AN:

1054423

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

340779

show subpopulations

African (AFR)

AF:

0.0000817

AC:

AN:

24472

American (AMR)

AF:

0.00

AC:

AN:

27574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16315

East Asian (EAS)

AF:

0.00

AC:

AN:

29910

South Asian (SAS)

AF:

0.00

AC:

AN:

46550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3774

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

823073

Other (OTH)

AF:

0.00

AC:

AN:

44075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34159

show subpopulations

African (AFR)

AF:

0.0000975

AC:

AN:

30783

American (AMR)

AF:

0.00

AC:

AN:

10623

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3591

South Asian (SAS)

AF:

0.00

AC:

AN:

2690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6071

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53195

Other (OTH)

AF:

0.00

AC:

AN:

1480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.30

CADD

Benign

7.2

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.12

MetaSVM

Uncertain

-0.039

MutationAssessor

Benign

0.90

PhyloP100

-0.46

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.5

REVEL

Benign

0.28

Sift

Benign

0.29

Sift4G

Benign

0.28

Polyphen

0.59

Vest4

0.24

MVP

0.83

MPC

0.23

ClinPred

0.050

GERP RS

-6.0

Varity_R

0.11

gMVP

0.19

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 25

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over