rs148239437

Positions:

• chrX-13760504-A-C
• chrX-13760504-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003611.3(OFD1):​c.2044A>C​(p.Ile682Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,166,792 control chromosomes in the GnomAD database, including 3 homozygotes. There are 121 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I682M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., 65 hem., cov: 22)
  • Exomes 𝑓: 0.00019 (1 hom. 56 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.340

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039521456).
• BP6: Variant X-13760504-A-C is Benign according to our data. Variant chrX-13760504-A-C is described in ClinVar as [Benign]. Clinvar id is 239545.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 = 0.00202 (226/111788) while in subpopulation AFR AF= 0.00705 (217/30779). AF 95% confidence interval is 0.00628. There are 2 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OFD1	NM_003611.3	c.2044A>C	p.Ile682Leu	missense_variant	16/23	ENST00000340096.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OFD1	ENST00000340096.11	c.2044A>C	p.Ile682Leu	missense_variant	16/23	1	NM_003611.3	P1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 226 AN: 111732 Hom.: 2 Cov.: 22 AF XY: 0.00192 AC XY: 65 AN XY: 33908

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000566

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: 0.0000377

Gnomad OTH AF: 0.000677

GnomAD3 exomes AF: 0.000725 AC: 105 AN: 144828 Hom.: 0 AF XY: 0.000583 AC XY: 28 AN XY: 48058

Gnomad AFR exome AF: 0.00770

Gnomad AMR exome AF: 0.000397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000923

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000297

GnomAD4 exome AF: 0.000186 AC: 196 AN: 1055004 Hom.: 1 Cov.: 31 AF XY: 0.000164 AC XY: 56 AN XY: 341480

Gnomad4 AFR exome AF: 0.00666

Gnomad4 AMR exome AF: 0.000435

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000214

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000486

Gnomad4 OTH exome AF: 0.000340

GnomAD4 genome AF: 0.00202 AC: 226 AN: 111788 Hom.: 2 Cov.: 22 AF XY: 0.00191 AC XY: 65 AN XY: 33974

Gnomad4 AFR AF: 0.00705

Gnomad4 AMR AF: 0.000565

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.000668

Alfa AF: 0.000703 Hom.: 5

Bravo AF: 0.00241

ESP6500AA AF: 0.00600 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000720 AC: 87

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 24, 2019	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.012
DANN	Benign	0.79
DEOGEN2	Benign	0.12	T;.;.
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.32	T;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.45	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.11	B;B;B
Vest4		0.16
MVP		0.64
MPC		0.14
ClinPred		0.0044	T
GERP RS		-3.0
Varity_R		0.068
gMVP		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs148239437; hg19: chrX-13778623;