X-13736597-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330210.2(OFD1):​c.-315A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: OFD1 NM_001330210.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• 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):

• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330210.2. 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.231A>G	p.Leu77Leu	synonymous	Exon 3 of 23	NP_003602.1	O75665-1
	OFD1	NM_001330210.2		c.-315A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 24	NP_001317139.1
	OFD1	NM_001440947.1		c.231A>G	p.Leu77Leu	synonymous	Exon 3 of 22	NP_001427876.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.231A>G	p.Leu77Leu	synonymous	Exon 3 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.231A>G	p.Leu77Leu	synonymous	Exon 3 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.231A>G	p.Leu77Leu	synonymous	Exon 3 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096727 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362105

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4131

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840744

Other (OTH) AF: 0.00 AC: 0 AN: 46058

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.45
DANN	Benign	0.72
PhyloP100		-0.39

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: rs587784232; hg19: chrX-13754716;