rs373792491

Variant names:

• chrX-13758428-A-G
• rs373792491
• NM_003611.3:c.1634A>G
• OFD1 p.Gln545Arg

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3 BP6 BS2_Supporting

The NM_003611.3(OFD1):​c.1634A>G​(p.Gln545Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000411 in 1,168,999 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000040 (0 hom. 17 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.86
• Publications: 3 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: 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 -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• BP6: Variant X-13758428-A-G is Benign according to our data. Variant chrX-13758428-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447888.
• BS2: High Hemizygotes in GnomAd4 at 2 XL,AD,AR geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1634A>G	p.Gln545Arg	missense	Exon 15 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.1634A>G	p.Gln545Arg	missense	Exon 15 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.1514A>G	p.Gln505Arg	missense	Exon 14 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.1634A>G	p.Gln545Arg	missense	Exon 15 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1514A>G	p.Gln505Arg	missense	Exon 14 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.1637A>G	p.Gln546Arg	missense	Exon 15 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.0000536 AC: 6 AN: 111894 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000493 AC: 9 AN: 182633 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.000536

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 42 AN: 1057105 Hom.: 0 Cov.: 25 AF XY: 0.0000522 AC XY: 17 AN XY: 325931

African (AFR) AF: 0.00 AC: 0 AN: 25675

American (AMR) AF: 0.0000569 AC: 2 AN: 35147

Ashkenazi Jewish (ASJ) AF: 0.000680 AC: 13 AN: 19131

East Asian (EAS) AF: 0.00 AC: 0 AN: 30019

South Asian (SAS) AF: 0.00 AC: 0 AN: 53087

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3361

European-Non Finnish (NFE) AF: 0.0000298 AC: 24 AN: 805429

Other (OTH) AF: 0.0000670 AC: 3 AN: 44761

GnomAD4 genome AF: 0.0000536 AC: 6 AN: 111894 Hom.: 0 Cov.: 22 AF XY: 0.0000587 AC XY: 2 AN XY: 34064

African (AFR) AF: 0.00 AC: 0 AN: 30778

American (AMR) AF: 0.0000950 AC: 1 AN: 10530

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53226

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.046	D
Varity_R		0.33
gMVP		0.41
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373792491;

hg19: chrX-13776547;