rs180940027

Variant names:

• chrX-13768700-C-T
• rs180940027
• NM_003611.3:c.2929-18C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003611.3(OFD1):​c.2929-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,190,821 control chromosomes in the GnomAD database, including 45 homozygotes. There are 3,109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (1 hom., 184 hem., cov: 23)
  • Exomes 𝑓: 0.0091 (44 hom. 2925 hem.)
• Consequence: OFD1 NM_003611.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.649
• 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):

• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-13768700-C-T is Benign according to our data. Variant chrX-13768700-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00601 (672/111804) while in subpopulation NFE AF = 0.00974 (518/53157). AF 95% confidence interval is 0.00905. There are 1 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 184 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.2929-18C>T		intron	N/A	NP_003602.1
	OFD1	NM_001440947.1		c.2818-18C>T		intron	N/A	NP_001427876.1
	OFD1	NM_001330209.2		c.2809-18C>T		intron	N/A	NP_001317138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.2929-18C>T		intron	N/A	ENSP00000344314.6
	OFD1	ENST00000380550.6	TSL:1	c.2809-18C>T		intron	N/A	ENSP00000369923.3
	OFD1	ENST00000683055.1		n.*5043C>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000508191.1

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 672 AN: 111752 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00351

Gnomad ASJ AF: 0.00907

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00974

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00678 AC: 1239 AN: 182862 AF XY: 0.00710

Gnomad AFR exome AF: 0.000913

Gnomad AMR exome AF: 0.00326

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00909 AC: 9810 AN: 1079017 Hom.: 44 Cov.: 27 AF XY: 0.00843 AC XY: 2925 AN XY: 347021

African (AFR) AF: 0.00119 AC: 31 AN: 26066

American (AMR) AF: 0.00387 AC: 136 AN: 35141

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 254 AN: 19255

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30121

South Asian (SAS) AF: 0.00239 AC: 128 AN: 53544

European-Finnish (FIN) AF: 0.00555 AC: 225 AN: 40518

Middle Eastern (MID) AF: 0.00735 AC: 30 AN: 4082

European-Non Finnish (NFE) AF: 0.0104 AC: 8581 AN: 824864

Other (OTH) AF: 0.00933 AC: 424 AN: 45426

GnomAD4 genome AF: 0.00601 AC: 672 AN: 111804 Hom.: 1 Cov.: 23 AF XY: 0.00541 AC XY: 184 AN XY: 34002

African (AFR) AF: 0.00114 AC: 35 AN: 30801

American (AMR) AF: 0.00350 AC: 37 AN: 10565

Ashkenazi Jewish (ASJ) AF: 0.00907 AC: 24 AN: 2646

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3585

South Asian (SAS) AF: 0.00150 AC: 4 AN: 2666

European-Finnish (FIN) AF: 0.00621 AC: 37 AN: 5961

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.00974 AC: 518 AN: 53157

Other (OTH) AF: 0.00988 AC: 15 AN: 1518

Alfa AF: 0.00796 Hom.: 64

Bravo AF: 0.00569

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Joubert syndrome;C1510460:Orofaciodigital syndrome I (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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.041
DANN	Benign	0.45
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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: rs180940027; hg19: chrX-13786819;