chrX-13736597-A-C

Variant names:

• chrX-13736597-A-C
• rs587784232
• NM_003611.3:c.231A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_003611.3(OFD1):​c.231A>C​(p.Leu77Phe) 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. L77S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.393
• Publications: 0 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):

• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a domain LisH (size 32) in uniprot entity OFD1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_003611.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-13736596-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 547065.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.231A>C	p.Leu77Phe	missense_variant	Exon 3 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.231A>C	p.Leu77Phe	missense_variant	Exon 3 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Orofaciodigital syndrome I Uncertain:1

Jun 20, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.6	L;L
PhyloP100		-0.39
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.23		Loss of stability (P = 0.1337);Loss of stability (P = 0.1337);
MVP		0.97
MPC		0.59
ClinPred		0.98	D
GERP RS		-11
Varity_R		0.83
gMVP		0.85
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs587784232; hg19: chrX-13754716;