rs886039860

Variant names:

• chrX-13744424-T-C
• rs886039860
• NM_003611.3:c.422T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-13744424-T-C
• chrX-13744424-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_001330210.2(OFD1):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000163 in 1,041,623 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: OFD1 NM_001330210.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.69
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 19 codons. Genomic position: 13744477. Lost 0.021 part of the original CDS.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL,AD,AR gene

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.422T>C	p.Met141Thr	missense	Exon 6 of 23	NP_003602.1
	OFD1	NM_001330210.2		c.2T>C	p.Met1?	start_lost	Exon 7 of 24	NP_001317139.1
	OFD1	NM_001440947.1		c.422T>C	p.Met141Thr	missense	Exon 6 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.422T>C	p.Met141Thr	missense	Exon 6 of 23	ENSP00000344314.6
	OFD1	ENST00000380550.6	TSL:1	c.422T>C	p.Met141Thr	missense	Exon 6 of 22	ENSP00000369923.3
	OFD1	ENST00000922714.1		c.422T>C	p.Met141Thr	missense	Exon 6 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181673 AF XY: 0.0000302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000163 AC: 17 AN: 1041623 Hom.: 0 Cov.: 23 AF XY: 0.0000185 AC XY: 6 AN XY: 324091

African (AFR) AF: 0.00 AC: 0 AN: 25338

American (AMR) AF: 0.00 AC: 0 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19030

East Asian (EAS) AF: 0.00 AC: 0 AN: 29962

South Asian (SAS) AF: 0.00 AC: 0 AN: 52795

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40467

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2783

European-Non Finnish (NFE) AF: 0.0000202 AC: 16 AN: 792039

Other (OTH) AF: 0.0000227 AC: 1 AN: 44075

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome;C1510460:Orofaciodigital syndrome I (1)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.31	D
PhyloP100		3.7
Sift4G	Uncertain	0.056	T
Vest4		0.49
MVP		0.84
ClinPred		0.73	D
GERP RS		5.2
Varity_R		0.27
Mutation Taster		=40/160	disease causing

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: rs886039860; hg19: chrX-13762543;