X-13760504-A-G

Variant names:

• chrX-13760504-A-G
• rs148239437
• NM_003611.3:c.2044A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003611.3(OFD1):​c.2044A>G​(p.Ile682Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000948 in 1,055,004 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I682L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.340
• 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):

• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0464105).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.2044A>G	p.Ile682Val	missense	Exon 16 of 23	NP_003602.1
	OFD1	NM_001440947.1		c.2044A>G	p.Ile682Val	missense	Exon 16 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.1924A>G	p.Ile642Val	missense	Exon 15 of 22	NP_001317138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.2044A>G	p.Ile682Val	missense	Exon 16 of 23	ENSP00000344314.6
	OFD1	ENST00000380550.6	TSL:1	c.1924A>G	p.Ile642Val	missense	Exon 15 of 22	ENSP00000369923.3
	OFD1	ENST00000380567.6	TSL:5	n.*1737A>G		non_coding_transcript_exon	Exon 17 of 24	ENSP00000369941.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00 AC: 0 AN: 144828 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.48e-7 AC: 1 AN: 1055004 Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 1 AN XY: 341480

African (AFR) AF: 0.00 AC: 0 AN: 24489

American (AMR) AF: 0.00 AC: 0 AN: 27566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16376

East Asian (EAS) AF: 0.00 AC: 0 AN: 29915

South Asian (SAS) AF: 0.0000214 AC: 1 AN: 46753

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38711

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3853

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 823235

Other (OTH) AF: 0.00 AC: 0 AN: 44106

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0040
DANN	Benign	0.22
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.34
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.13
Sift	Benign	0.43	T
Sift4G	Benign	0.79	T
Polyphen		0.0080	B
Vest4		0.085
MutPred		0.13		Gain of ubiquitination at K680 (P = 0.069)
MVP		0.43
MPC		0.10
ClinPred		0.025	T
GERP RS		-3.0
Varity_R		0.034
gMVP		0.063
Mutation Taster		=97/3	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: rs148239437; hg19: chrX-13778623;