NM_003611.3:c.1303A>C

Variant names:

• chrX-13756659-A-C
• rs122460150
• NM_003611.3:c.1303A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_003611.3(OFD1):​c.1303A>C​(p.Ser435Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.38
• Publications: 6 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• PP5: Variant X-13756659-A-C is Pathogenic according to our data. Variant chrX-13756659-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11537.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.1303A>C	p.Ser435Arg	missense	Exon 13 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.1303A>C	p.Ser435Arg	missense	Exon 13 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.1183A>C	p.Ser395Arg	missense	Exon 12 of 22	NP_001317138.1	O75665-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.1303A>C	p.Ser435Arg	missense	Exon 13 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1183A>C	p.Ser395Arg	missense	Exon 12 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.1306A>C	p.Ser436Arg	missense	Exon 13 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Orofaciodigital syndrome I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.67
Sift	Benign	0.17	T
Sift4G	Benign	0.58	T
Polyphen		0.51	P
Vest4		0.57
MutPred		0.68		Loss of phosphorylation at S435 (P = 0.0415)
MVP		0.98
MPC		0.52
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.35
gMVP		0.26
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs122460150; hg19: chrX-13774778;