rs201761130

Variant names:

• chrX-13758318-C-G
• rs201761130
• NM_003611.3:c.1543-19C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-13758318-C-G
• chrX-13758318-C-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003611.3(OFD1):​c.1543-19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,049,732 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 180 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., 13 hem., cov: 22)
  • Exomes 𝑓: 0.00059 (0 hom. 167 hem.)
• Consequence: OFD1 NM_003611.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.687
• 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: Benign. The variant received -16 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-13758318-C-G is Benign according to our data. Variant chrX-13758318-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 13 XL,AD,AR gene

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.1543-19C>G		intron	N/A	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.1543-19C>G		intron	N/A	NP_001427876.1
	OFD1	NM_001330209.2		c.1423-19C>G		intron	N/A	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.1543-19C>G		intron	N/A	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1423-19C>G		intron	N/A	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.1546-19C>G		intron	N/A	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.000413 AC: 46 AN: 111256 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000715

Gnomad OTH AF: 0.000672

GnomAD2 exomes AF: 0.000312 AC: 56 AN: 179539 AF XY: 0.000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000547

Gnomad OTH exome AF: 0.000451

GnomAD4 exome AF: 0.000585 AC: 549 AN: 938421 Hom.: 0 Cov.: 16 AF XY: 0.000628 AC XY: 167 AN XY: 265769

African (AFR) AF: 0.00 AC: 0 AN: 23295

American (AMR) AF: 0.000374 AC: 13 AN: 34731

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18339

East Asian (EAS) AF: 0.00 AC: 0 AN: 29452

South Asian (SAS) AF: 0.00 AC: 0 AN: 50142

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40381

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3663

European-Non Finnish (NFE) AF: 0.000741 AC: 517 AN: 697694

Other (OTH) AF: 0.000442 AC: 18 AN: 40724

GnomAD4 genome AF: 0.000413 AC: 46 AN: 111311 Hom.: 0 Cov.: 22 AF XY: 0.000388 AC XY: 13 AN XY: 33513

African (AFR) AF: 0.0000652 AC: 2 AN: 30680

American (AMR) AF: 0.000479 AC: 5 AN: 10439

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000715 AC: 38 AN: 53111

Other (OTH) AF: 0.000664 AC: 1 AN: 1507

Alfa AF: 0.000695 Hom.: 5

Bravo AF: 0.000480

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.3
DANN	Benign	0.64
PhyloP100		0.69
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201761130; hg19: chrX-13776437;