rs763219658

Variant names:

• chrX-13738857-G-A
• rs763219658
• NM_003611.3:c.324G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_003611.3(OFD1):​c.324G>A​(p.Met108Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,160,011 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. 14/21 in silico tools predict 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: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.43
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-13738857-G-A is Pathogenic according to our data. Variant chrX-13738857-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 571289.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17313766). . Strength limited to SUPPORTING due to the PP5.

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.324G>A	p.Met108Ile	missense	Exon 4 of 23	NP_003602.1
	OFD1	NM_001440947.1		c.324G>A	p.Met108Ile	missense	Exon 4 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.324G>A	p.Met108Ile	missense	Exon 4 of 22	NP_001317138.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.324G>A	p.Met108Ile	missense	Exon 4 of 23	ENSP00000344314.6
	OFD1	ENST00000380550.6	TSL:1	c.324G>A	p.Met108Ile	missense	Exon 4 of 22	ENSP00000369923.3
	OFD1	ENST00000922714.1		c.324G>A	p.Met108Ile	missense	Exon 4 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111779 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182340 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: 0.000222

GnomAD4 exome AF: 0.00000191 AC: 2 AN: 1048232 Hom.: 0 Cov.: 25 AF XY: 0.00000305 AC XY: 1 AN XY: 327822

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25390

American (AMR) AF: 0.00 AC: 0 AN: 35088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19063

East Asian (EAS) AF: 0.00 AC: 0 AN: 29889

South Asian (SAS) AF: 0.0000379 AC: 2 AN: 52747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2785

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 798369

Other (OTH) AF: 0.00 AC: 0 AN: 44399

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111779 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 33987

African (AFR) AF: 0.00 AC: 0 AN: 30758

American (AMR) AF: 0.000190 AC: 2 AN: 10526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3617

South Asian (SAS) AF: 0.00 AC: 0 AN: 2749

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5937

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53124

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome;C1510460:Orofaciodigital syndrome I (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Retinitis pigmentosa 23;C1510460:Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.17	T
Polyphen		0.17	B
Vest4		0.29
MutPred		0.34		Loss of ubiquitination at K104 (P = 0.1055)
MVP		0.92
MPC		0.39
ClinPred		0.24	T
GERP RS		4.1
Varity_R		0.24
gMVP		0.34
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs763219658; hg19: chrX-13756976;