rs149473481

Variant names:

• chrX-13760485-G-T
• rs149473481
• NM_003611.3:c.2025G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_003611.3(OFD1):​c.2025G>T​(p.Leu675Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,167,305 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 7 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.13
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.110373855).
• BP6: Variant X-13760485-G-T is Benign according to our data. Variant chrX-13760485-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 463453.
• BS2: High Hemizygotes in GnomAdExome4 at 7 XL,AD,AR gene

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.2025G>T	p.Leu675Phe	missense	Exon 16 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.2025G>T	p.Leu675Phe	missense	Exon 16 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.1905G>T	p.Leu635Phe	missense	Exon 15 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.2025G>T	p.Leu675Phe	missense	Exon 16 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1905G>T	p.Leu635Phe	missense	Exon 15 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.2028G>T	p.Leu676Phe	missense	Exon 16 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111928 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000206 AC: 3 AN: 145754 AF XY: 0.0000414

Gnomad AFR exome AF: 0.0000811

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: 0.0000146

Gnomad OTH exome AF: 0.000293

GnomAD4 exome AF: 0.0000237 AC: 25 AN: 1055377 Hom.: 0 Cov.: 31 AF XY: 0.0000205 AC XY: 7 AN XY: 341061

African (AFR) AF: 0.0000408 AC: 1 AN: 24496

American (AMR) AF: 0.00 AC: 0 AN: 27705

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16397

East Asian (EAS) AF: 0.00 AC: 0 AN: 29904

South Asian (SAS) AF: 0.00 AC: 0 AN: 46735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38728

Middle Eastern (MID) AF: 0.000535 AC: 2 AN: 3740

European-Non Finnish (NFE) AF: 0.0000219 AC: 18 AN: 823553

Other (OTH) AF: 0.0000907 AC: 4 AN: 44119

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111928 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34084

African (AFR) AF: 0.0000325 AC: 1 AN: 30760

American (AMR) AF: 0.00 AC: 0 AN: 10612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53195

Other (OTH) AF: 0.00 AC: 0 AN: 1481

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-1.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.29
Sift	Benign	0.071	T
Sift4G	Benign	0.11	T
Polyphen		0.71	P
Vest4		0.12
MutPred		0.12		Loss of ubiquitination at K680 (P = 0.1202)
MVP		0.85
MPC		0.15
ClinPred		0.047	T
GERP RS		-1.5
Varity_R		0.10
gMVP		0.10
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149473481; hg19: chrX-13778604;