rs146251034

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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P687P) has been classified as Likely benign.

• 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]

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 GnomAd at 4 XL gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OFD1	ENST00000340096.11	c.2060C>T	p.Pro687Leu	missense_variant	16/23	1	NM_003611.3	P1

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	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	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Invitae

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;.;.
MutationTaster	Benign	1.0	N;N;N
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;