X-13735053-C-G

Variant names:

• chrX-13735053-C-G
• rs377742225
• NM_003611.3:c.-19C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003611.3(OFD1):​c.-19C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000623 in 1,187,217 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 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 0.00027 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.000041 (0 hom. 18 hem.)
• Consequence: OFD1 NM_003611.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-13735053-C-G is Benign according to our data. Variant chrX-13735053-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 680448.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 3 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.-19C>G		5_prime_UTR_variant	Exon 1 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.-19C>G		5_prime_UTR_variant	Exon 1 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes AF: 0.000267 AC: 30 AN: 112499 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000371

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000144 AC: 21 AN: 145361 AF XY: 0.000107

Gnomad AFR exome AF: 0.000961

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000646

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000409 AC: 44 AN: 1074664 Hom.: 0 Cov.: 31 AF XY: 0.0000512 AC XY: 18 AN XY: 351440

African (AFR) AF: 0.000308 AC: 8 AN: 26007

American (AMR) AF: 0.000291 AC: 10 AN: 34368

Ashkenazi Jewish (ASJ) AF: 0.0000523 AC: 1 AN: 19129

East Asian (EAS) AF: 0.00 AC: 0 AN: 29460

South Asian (SAS) AF: 0.0000189 AC: 1 AN: 52897

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30660

Middle Eastern (MID) AF: 0.000561 AC: 2 AN: 3563

European-Non Finnish (NFE) AF: 0.0000192 AC: 16 AN: 833353

Other (OTH) AF: 0.000133 AC: 6 AN: 45227

GnomAD4 genome AF: 0.000267 AC: 30 AN: 112553 Hom.: 0 Cov.: 24 AF XY: 0.0000864 AC XY: 3 AN XY: 34709

African (AFR) AF: 0.000612 AC: 19 AN: 31041

American (AMR) AF: 0.000371 AC: 4 AN: 10789

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

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

South Asian (SAS) AF: 0.000372 AC: 1 AN: 2688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53208

Other (OTH) AF: 0.00131 AC: 2 AN: 1532

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000355

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.0
DANN	Benign	0.65
PhyloP100		1.3
PromoterAI		-0.0057	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs377742225; hg19: chrX-13753172;