NM_003611.3:c.1100G>C

Variant names:

• chrX-13753412-G-C
• rs312262864
• NM_003611.3:c.1100G>C

Variant summary

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

The NM_003611.3(OFD1):​c.1100G>C​(p.Arg367Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.170
• Publications: 2 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 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.1100G>C	p.Arg367Pro	missense	Exon 11 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.1100G>C	p.Arg367Pro	missense	Exon 11 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.980G>C	p.Arg327Pro	missense	Exon 10 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.1100G>C	p.Arg367Pro	missense	Exon 11 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.980G>C	p.Arg327Pro	missense	Exon 10 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.1103G>C	p.Arg368Pro	missense	Exon 11 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Benign	0.087	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.17
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.36		Loss of MoRF binding (P = 0.0666)
MVP		0.87
MPC		0.59
ClinPred		0.94	D
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.64
gMVP		0.60
Mutation Taster		=60/40	polymorphism

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: rs312262864; hg19: chrX-13771531;