X-13735111-G-C

Variant names:

• chrX-13735111-G-C
• rs181620366
• NM_003611.3:c.12+28G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003611.3(OFD1):​c.12+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,205,500 control chromosomes in the GnomAD database, including 2 homozygotes. There are 96 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 0.0019 (1 hom., 52 hem., cov: 24)
  • Exomes 𝑓: 0.00019 (1 hom. 44 hem.)
• Consequence: OFD1 NM_003611.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.680
• Publications: 0 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-13735111-G-C is Benign according to our data. Variant chrX-13735111-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 211784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00193 (217/112722) while in subpopulation AFR AF = 0.00624 (194/31095). AF 95% confidence interval is 0.00552. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 52 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.12+28G>C		intron_variant	Intron 1 of 22	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.12+28G>C		intron_variant	Intron 1 of 22	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 217 AN: 112668 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00167

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: 0.0000188

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.000538 AC: 92 AN: 171010 AF XY: 0.000278

Gnomad AFR exome AF: 0.00628

Gnomad AMR exome AF: 0.000519

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000193 AC: 211 AN: 1092778 Hom.: 1 Cov.: 31 AF XY: 0.000122 AC XY: 44 AN XY: 359526

African (AFR) AF: 0.00623 AC: 164 AN: 26323

American (AMR) AF: 0.000571 AC: 20 AN: 35023

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19326

East Asian (EAS) AF: 0.00 AC: 0 AN: 30061

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38219

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4065

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840208

Other (OTH) AF: 0.000501 AC: 23 AN: 45897

GnomAD4 genome AF: 0.00193 AC: 217 AN: 112722 Hom.: 1 Cov.: 24 AF XY: 0.00149 AC XY: 52 AN XY: 34886

African (AFR) AF: 0.00624 AC: 194 AN: 31095

American (AMR) AF: 0.00167 AC: 18 AN: 10784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53246

Other (OTH) AF: 0.00262 AC: 4 AN: 1525

Alfa AF: 0.000261 Hom.: 2

Bravo AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 05, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 14, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		0.68
PromoterAI		-0.21	Neutral
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: rs181620366; hg19: chrX-13753230;