rs312262857

Variant names:

• chrX-13749469-A-G
• rs312262857
• NM_003611.3:c.871A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-13749469-A-G
• chrX-13749469-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003611.3(OFD1):​c.871A>G​(p.Lys291Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,088,173 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33
• Publications: 3 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.871A>G	p.Lys291Glu	missense	Exon 9 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.871A>G	p.Lys291Glu	missense	Exon 9 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.871A>G	p.Lys291Glu	missense	Exon 9 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.871A>G	p.Lys291Glu	missense	Exon 9 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.871A>G	p.Lys291Glu	missense	Exon 9 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.874A>G	p.Lys292Glu	missense	Exon 9 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183106 AF XY: 0.0000148

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: 0.0000625

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1088173 Hom.: 0 Cov.: 27 AF XY: 0.00000282 AC XY: 1 AN XY: 355079

African (AFR) AF: 0.00 AC: 0 AN: 26207

American (AMR) AF: 0.00 AC: 0 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19310

East Asian (EAS) AF: 0.00 AC: 0 AN: 30091

South Asian (SAS) AF: 0.00 AC: 0 AN: 53857

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2953

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 834356

Other (OTH) AF: 0.00 AC: 0 AN: 45689

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.42
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.22		Loss of ubiquitination at K291 (P = 0.0167)
MVP		0.95
MPC		0.64
ClinPred		0.75	D
GERP RS		5.5
Varity_R		0.61
gMVP		0.34
Mutation Taster		=67/33	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: rs312262857; hg19: chrX-13767588;