chrX-13735075-A-G

Variant names:

• chrX-13735075-A-G
• rs2046800711
• NM_003611.3:c.4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003611.3(OFD1):​c.4A>G​(p.Met2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,509 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0840
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27778858).

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.4A>G	p.Met2Val	missense	Exon 1 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.4A>G	p.Met2Val	missense	Exon 1 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.4A>G	p.Met2Val	missense	Exon 1 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.4A>G	p.Met2Val	missense	Exon 1 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.4A>G	p.Met2Val	missense	Exon 1 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.4A>G	p.Met2Val	missense	Exon 1 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1084509 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 356077

African (AFR) AF: 0.00 AC: 0 AN: 26223

American (AMR) AF: 0.00 AC: 0 AN: 34848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19263

East Asian (EAS) AF: 0.00 AC: 0 AN: 29919

South Asian (SAS) AF: 0.00 AC: 0 AN: 53369

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33331

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3833

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 838057

Other (OTH) AF: 0.00 AC: 0 AN: 45666

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.18
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	5.8
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.016	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.084
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.31
Sift	Benign	0.14	T
Sift4G	Benign	0.068	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.25		Loss of disorder (P = 0.1146)
MVP		0.95
MPC		0.17
ClinPred		0.10	T
GERP RS		2.0
PromoterAI		-0.078	Neutral
Varity_R		0.17
gMVP		0.44
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2046800711; hg19: chrX-13753194;