X-13736564-G-T

Variant names:

• chrX-13736564-G-T
• rs776103115
• NM_003611.3:c.198G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003611.3(OFD1):​c.198G>T​(p.Gly66Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. G66G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OFD1 NM_003611.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0890
• 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):

• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.198G>T	p.Gly66Gly	synonymous	Exon 3 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.198G>T	p.Gly66Gly	synonymous	Exon 3 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.198G>T	p.Gly66Gly	synonymous	Exon 3 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.198G>T	p.Gly66Gly	synonymous	Exon 3 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.198G>T	p.Gly66Gly	synonymous	Exon 3 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.198G>T	p.Gly66Gly	synonymous	Exon 3 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	18
DANN	Benign	0.58
PhyloP100		-0.089

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: -2

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

Other links and lift over

dbSNP: rs776103115; hg19: chrX-13754683;