X-13735251-A-G

Variant names:

• chrX-13735251-A-G
• rs148995835
• NM_003611.3:c.16A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003611.3(OFD1):​c.16A>G​(p.Asn6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,251 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N6S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078596115).

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.16A>G	p.Asn6Asp	missense	Exon 2 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.16A>G	p.Asn6Asp	missense	Exon 2 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.16A>G	p.Asn6Asp	missense	Exon 2 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.16A>G	p.Asn6Asp	missense	Exon 2 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.16A>G	p.Asn6Asp	missense	Exon 2 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.16A>G	p.Asn6Asp	missense	Exon 2 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097251 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362615

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54123

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841231

Other (OTH) AF: 0.00 AC: 0 AN: 46067

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.74
DEOGEN2	Benign	0.068	T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.079	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.14
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.12	B
Vest4		0.087
MVP		0.80
MPC		0.17
ClinPred		0.076	T
GERP RS		1.4
PromoterAI		0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.079
gMVP		0.24
Mutation Taster		=94/6	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: rs148995835; hg19: chrX-13753370;