rs147114577

Variant names:

• chrX-13735289-A-G
• rs147114577
• NM_003611.3:c.54A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-13735289-A-G
• chrX-13735289-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_003611.3(OFD1):​c.54A>G​(p.Glu18Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,210,364 control chromosomes in the GnomAD database, including 1 homozygotes. There are 130 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 0.00025 (0 hom., 8 hem., cov: 24)
  • Exomes 𝑓: 0.00034 (1 hom. 122 hem.)
• Consequence: OFD1 NM_003611.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.972
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-13735289-A-G is Benign according to our data. Variant chrX-13735289-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94373.
• BP7: Synonymous conserved (PhyloP=-0.972 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 8 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.54A>G	p.Glu18Glu	synonymous	Exon 2 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.54A>G	p.Glu18Glu	synonymous	Exon 2 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.54A>G	p.Glu18Glu	synonymous	Exon 2 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.54A>G	p.Glu18Glu	synonymous	Exon 2 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.54A>G	p.Glu18Glu	synonymous	Exon 2 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.54A>G	p.Glu18Glu	synonymous	Exon 2 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.000249 AC: 28 AN: 112381 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000937

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000488

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000381 AC: 70 AN: 183529 AF XY: 0.000338

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000671

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000343 AC: 377 AN: 1097983 Hom.: 1 Cov.: 29 AF XY: 0.000336 AC XY: 122 AN XY: 363337

African (AFR) AF: 0.0000379 AC: 1 AN: 26399

American (AMR) AF: 0.000369 AC: 13 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.000197 AC: 8 AN: 40532

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4137

European-Non Finnish (NFE) AF: 0.000407 AC: 343 AN: 841888

Other (OTH) AF: 0.000239 AC: 11 AN: 46088

GnomAD4 genome AF: 0.000249 AC: 28 AN: 112381 Hom.: 0 Cov.: 24 AF XY: 0.000232 AC XY: 8 AN XY: 34539

African (AFR) AF: 0.00 AC: 0 AN: 30919

American (AMR) AF: 0.0000937 AC: 1 AN: 10671

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3607

South Asian (SAS) AF: 0.00 AC: 0 AN: 2752

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000488 AC: 26 AN: 53251

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.000353 Hom.: 6

Bravo AF: 0.000238

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.9
DANN	Benign	0.71
PhyloP100		-0.97
PromoterAI		0.027	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147114577; hg19: chrX-13753408;