NM_003611.3:c.710delA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_003611.3(OFD1):c.710delA(p.Lys237SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,065,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000067 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

OFD1
NM_003611.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.15

Publications

11 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant X-13746826-CA-C is Pathogenic according to our data. Variant chrX-13746826-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 41142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3 link	c.710delA	p.Lys237SerfsTer6	frameshift_variant	Exon 8 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.710delA	p.Lys237SerfsTer6	frameshift_variant	Exon 8 of 23	1	NM_003611.3	ENSP00000344314.6		O75665-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

106939

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.000198

AC:

AN:

151766

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000877

Gnomad AMR exome

AF:

0.000697

Gnomad ASJ exome

AF:

0.000164

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000667

AC:

AN:

1065099

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342117

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000356

AC:

AN:

25282

American (AMR)

AF:

0.000422

AC:

AN:

33188

Ashkenazi Jewish (ASJ)

AF:

0.0000534

AC:

AN:

18723

East Asian (EAS)

AF:

0.00

AC:

AN:

29503

South Asian (SAS)

AF:

0.0000594

AC:

AN:

50479

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39931

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4002

European-Non Finnish (NFE)

AF:

0.0000525

AC:

AN:

819294

Other (OTH)

AF:

0.0000224

AC:

AN:

44697

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.231

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

106939

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

30647

African (AFR)

AF:

0.00

AC:

AN:

29318

American (AMR)

AF:

0.00

AC:

AN:

10051

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2582

East Asian (EAS)

AF:

0.00

AC:

AN:

3478

South Asian (SAS)

AF:

0.00

AC:

AN:

2471

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5171

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51538

Other (OTH)

AF:

0.00

AC:

AN:

1428

Alfa

AF:

0.00130

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

OFD1-related disorder

Pathogenic:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The OFD1 c.710delA variant is predicted to result in a frameshift and premature protein termination (p.Lys237Serfs*6). This variant has been reported as having arisen de novo in at least two individuals with oral-facial-digital syndrome type 1 (Prattichizzo et al. 2008. PubMed ID: 18546297; Alby et al. 2018. PubMed ID: 29193896). This variant is reported in 0.068% of alleles in individuals of Latino descent in gnomAD; however, the quality of data at this position is questionable and should be interpreted with caution. Frameshift variants in OFD1 are expected to be pathogenic. This variant is classified as pathogenic. -

COACH syndrome

Pathogenic:1

Credence Genomics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome;C1510460:Orofaciodigital syndrome I

Pathogenic:1

Jul 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 41142). This sequence change creates a premature translational stop signal (p.Lys237Serfs*6) in the OFD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OFD1 are known to be pathogenic (PMID: 16783569, 18546297, 27081566). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with oral-facial-digital syndrome type I (PMID: 18546297). In at least one individual the variant was observed to be de novo. -

Orofaciodigital syndrome I

Pathogenic:1

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with orofaciodigital syndrome I (MIM#311200). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are X-linked recessive; however, orofaciodigital syndrome I (MIM#311200) is X-linked dominant. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variants have been associated with several OFD1-related conditions and are known to have intrafamilial and interfamilial variability (PMID: 31373179; PMID: 23033313). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001; however, the data quality of this variant is poor in gnomAD and is likely to be an artefact. (I) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in ClinVar as pathogenic, and reported as de novo in at least two individuals with OFDI syndrome (PMID: 29193896, PMID: 18546297). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: -46

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over