rs2046800981

Variant names:

• chrX-13735078-G-T
• rs2046800981
• NM_003611.3:c.7G>T

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.7G>T​(p.Ala3Ser) 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 1,085,327 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. 14/21 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. A3E) has been classified 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: 0.617
• 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):

• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092882335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085327 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 356503

African (AFR) AF: 0.0000381 AC: 1 AN: 26244

American (AMR) AF: 0.00 AC: 0 AN: 34852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19275

East Asian (EAS) AF: 0.00 AC: 0 AN: 29940

South Asian (SAS) AF: 0.00 AC: 0 AN: 53415

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33594

Middle Eastern (MID) AF: 0.000259 AC: 1 AN: 3857

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838461

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

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome;C1510460:Orofaciodigital syndrome I Uncertain:1

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with OFD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3 of the OFD1 protein (p.Ala3Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	T;.
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Uncertain	0.078	D
MutationAssessor	Benign	1.2	L;L
PhyloP100		0.62
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.20	N;N
REVEL	Benign	0.27
Sift	Benign	0.23	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.77	P;P
Vest4		0.050
MutPred		0.078		Gain of disorder (P = 0.0328);Gain of disorder (P = 0.0328);
MVP		0.81
MPC		0.13
ClinPred		0.20	T
GERP RS		2.3
PromoterAI		0.035	Neutral
Varity_R		0.066
gMVP		0.35
Mutation Taster		=91/9	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: rs2046800981; hg19: chrX-13753197;