rs750984782

Variant names:

• chrX-13760637-G-A
• rs750984782
• NM_003611.3:c.2177G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-13760637-G-A
• chrX-13760637-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003611.3(OFD1):​c.2177G>A​(p.Arg726His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000562 in 1,209,609 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R726C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000059 (0 hom. 22 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0300
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07958102).
• BS2: High Hemizygotes in GnomAdExome4 at 22 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.2177G>A	p.Arg726His	missense	Exon 16 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.2177G>A	p.Arg726His	missense	Exon 16 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.2057G>A	p.Arg686His	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.2177G>A	p.Arg726His	missense	Exon 16 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.2057G>A	p.Arg686His	missense	Exon 15 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.2180G>A	p.Arg727His	missense	Exon 16 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111845 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000941

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 3 AN: 181834 AF XY: 0.0000298

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: 0.0000248

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000592 AC: 65 AN: 1097764 Hom.: 0 Cov.: 31 AF XY: 0.0000606 AC XY: 22 AN XY: 363128

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000689 AC: 58 AN: 841747

Other (OTH) AF: 0.000130 AC: 6 AN: 46079

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111845 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34029

African (AFR) AF: 0.00 AC: 0 AN: 30696

American (AMR) AF: 0.0000941 AC: 1 AN: 10632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6071

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

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53124

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.017
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.080	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.030
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.21
Sift	Benign	0.38	T
Sift4G	Benign	0.17	T
Polyphen		0.025	B
Vest4		0.085
MutPred		0.31		Loss of methylation at R726 (P = 0.013)
MVP		0.78
MPC		0.16
ClinPred		0.022	T
GERP RS		-0.94
Varity_R		0.028
gMVP		0.17
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs750984782; hg19: chrX-13778756;