rs146251034

Positions:

• chrX-13760520-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003611.3(OFD1):​c.2060C>T​(p.Pro687Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,168,685 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 52 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 48 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.262

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029245377).
• BP6: Variant X-13760520-C-T is Benign according to our data. Variant chrX-13760520-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376777.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chrX-13760520-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OFD1	NM_003611.3	c.2060C>T	p.Pro687Leu	missense_variant	16/23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.2060C>T	p.Pro687Leu	missense_variant	16/23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 16 AN: 111803 Hom.: 0 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33983

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: 0.000332

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000245

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000300 AC: 44 AN: 146704 Hom.: 0 AF XY: 0.000269 AC XY: 13 AN XY: 48346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000973

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000366

Gnomad NFE exome AF: 0.000508

Gnomad OTH exome AF: 0.000582

GnomAD4 exome AF: 0.000162 AC: 171 AN: 1056882 Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 48 AN XY: 341948

Gnomad4 AFR exome AF: 0.0000815

Gnomad4 AMR exome AF: 0.0000717

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000283

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.000226

GnomAD4 genome AF: 0.000143 AC: 16 AN: 111803 Hom.: 0 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33983

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000941

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000332

Gnomad4 NFE AF: 0.000245

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 2

Bravo AF: 0.000140

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000331 AC: 40

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -

History of neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2012

There is insufficient or conflicting evidence for classification of this alteration. -

Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.3
DANN	Benign	0.30
DEOGEN2	Benign	0.14	T;.;.
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.95	L;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.011	B;B;B
Vest4		0.074
MVP		0.58
MPC		0.13
ClinPred		0.017	T
GERP RS		-3.9
Varity_R		0.031
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs146251034; hg19: chrX-13778639;