rs200465596

Variant names:

• chrX-13760190-A-G
• rs200465596
• NM_003611.3:c.1730A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003611.3(OFD1):​c.1730A>G​(p.Asn577Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,210,267 control chromosomes in the GnomAD database, including 1 homozygotes. There are 54 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. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N577K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (1 hom. 48 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0780
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031745434).
• BP6: Variant X-13760190-A-G is Benign according to our data. Variant chrX-13760190-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 6 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.1730A>G	p.Asn577Ser	missense	Exon 16 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.1730A>G	p.Asn577Ser	missense	Exon 16 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.1610A>G	p.Asn537Ser	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.1730A>G	p.Asn577Ser	missense	Exon 16 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1610A>G	p.Asn537Ser	missense	Exon 15 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.1733A>G	p.Asn578Ser	missense	Exon 16 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.000169 AC: 19 AN: 112244 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000943

Gnomad ASJ AF: 0.00565

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000316 AC: 58 AN: 183509 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000732

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.000160 AC: 176 AN: 1098023 Hom.: 1 Cov.: 31 AF XY: 0.000132 AC XY: 48 AN XY: 363379

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00676 AC: 131 AN: 19383

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000285 AC: 24 AN: 841930

Other (OTH) AF: 0.000412 AC: 19 AN: 46091

GnomAD4 genome AF: 0.000169 AC: 19 AN: 112244 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34420

African (AFR) AF: 0.00 AC: 0 AN: 30846

American (AMR) AF: 0.0000943 AC: 1 AN: 10599

Ashkenazi Jewish (ASJ) AF: 0.00565 AC: 15 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3592

South Asian (SAS) AF: 0.00 AC: 0 AN: 2738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6108

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

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53281

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.000678 Hom.: 4

Bravo AF: 0.000193

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ciliopathy (1)
-	-	1	OFD1-related disorder (1)
-	-	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	0.076
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.053
DANN	Benign	0.48
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0032	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.078
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.20
Sift	Benign	0.25	T
Sift4G	Benign	0.074	T
Polyphen		0.13	B
Vest4		0.041
MVP		0.50
MPC		0.10
ClinPred		0.027	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.028
Mutation Taster		=100/0	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: rs200465596; hg19: chrX-13778309;