chrX-13760512-C-T

Variant names:

• chrX-13760512-C-T
• rs61742891
• NM_003611.3:c.2052C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003611.3(OFD1):​c.2052C>T​(p.Ser684Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,167,500 control chromosomes in the GnomAD database, including 25 homozygotes. There are 551 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S684S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0095 (12 hom., 288 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (13 hom. 263 hem.)
• Consequence: OFD1 NM_003611.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.50
• 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: G2P, Labcorp Genetics (formerly Invitae)
• OFD1-related ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• orofaciodigital syndrome I

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-13760512-C-T is Benign according to our data. Variant chrX-13760512-C-T is described in ClinVar as Benign. ClinVar VariationId is 159468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00951 (1064/111889) while in subpopulation AFR AF = 0.0328 (1008/30733). AF 95% confidence interval is 0.0311. There are 12 homozygotes in GnomAd4. There are 288 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.2052C>T	p.Ser684Ser	synonymous	Exon 16 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.2052C>T	p.Ser684Ser	synonymous	Exon 16 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.1932C>T	p.Ser644Ser	synonymous	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.2052C>T	p.Ser684Ser	synonymous	Exon 16 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1932C>T	p.Ser644Ser	synonymous	Exon 15 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.2055C>T	p.Ser685Ser	synonymous	Exon 16 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.00953 AC: 1066 AN: 111835 Hom.: 12 Cov.: 23

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00423

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00405

GnomAD2 exomes AF: 0.00336 AC: 491 AN: 146019 AF XY: 0.00237

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000874

GnomAD4 exome AF: 0.00103 AC: 1090 AN: 1055611 Hom.: 13 Cov.: 31 AF XY: 0.000770 AC XY: 263 AN XY: 341475

African (AFR) AF: 0.0356 AC: 873 AN: 24521

American (AMR) AF: 0.00259 AC: 72 AN: 27761

Ashkenazi Jewish (ASJ) AF: 0.000122 AC: 2 AN: 16438

East Asian (EAS) AF: 0.00 AC: 0 AN: 29915

South Asian (SAS) AF: 0.0000213 AC: 1 AN: 46897

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38751

Middle Eastern (MID) AF: 0.00232 AC: 9 AN: 3886

European-Non Finnish (NFE) AF: 0.0000243 AC: 20 AN: 823323

Other (OTH) AF: 0.00256 AC: 113 AN: 44119

GnomAD4 genome AF: 0.00951 AC: 1064 AN: 111889 Hom.: 12 Cov.: 23 AF XY: 0.00846 AC XY: 288 AN XY: 34057

African (AFR) AF: 0.0328 AC: 1008 AN: 30733

American (AMR) AF: 0.00422 AC: 45 AN: 10656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2687

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6019

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53161

Other (OTH) AF: 0.00399 AC: 6 AN: 1502

Alfa AF: 0.000350 Hom.: 2

Bravo AF: 0.0108

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Joubert syndrome;C1510460:Orofaciodigital syndrome I (1)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.070
DANN	Benign	0.34
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61742891; hg19: chrX-13778631;