rs142352920

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_003611.3(OFD1):c.1294A>G(p.Lys432Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,203,364 control chromosomes in the GnomAD database, including 1 homozygotes. There are 170 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00050 ( 1 hom. 163 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.25

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09368104).

BP6

Variant X-13756650-A-G is Benign according to our data. Variant chrX-13756650-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 188156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-13756650-A-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3 link	c.1294A>G	p.Lys432Glu	missense_variant	Exon 13 of 23	ENST00000340096.11	NP_003602.1	O75665-1E9KL37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11 link	c.1294A>G	p.Lys432Glu	missense_variant	Exon 13 of 23	1	NM_003611.3	ENSP00000344314.6		O75665-1

Frequencies

GnomAD3 genomes

AF:

0.000249

AC:

AN:

112459

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

34603

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000563

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:

0.000375

Gnomad OTH

AF:

0.000667

GnomAD3 exomes

AF:

0.000177

AC:

AN:

181152

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

65894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000500

AC:

545

AN:

1090851

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

163

AN XY:

356785

show subpopulations

Gnomad4 AFR exome

AF:

0.000115

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000611

Gnomad4 OTH exome

AF:

0.000524

GnomAD4 genome

AF:

0.000249

AC:

AN:

112513

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

34667

show subpopulations

Gnomad4 AFR

AF:

0.0000323

Gnomad4 AMR

AF:

0.000562

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000375

Gnomad4 OTH

AF:

0.000658

Alfa

AF:

0.000406

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

OFD1-related disorder

Benign:1

Feb 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Nov 28, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Mar 31, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OFD1: BS2 -

Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 23;C1510460:Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10

Benign:1

Mar 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;.;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.094

T;T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.9

L;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

N;N;N;.

REVEL

Benign

0.25

Sift

Benign

0.17

T;T;T;.

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.25

B;P;B;.

Vest4

0.18

MVP

0.90

MPC

0.29

ClinPred

0.089

GERP RS

3.7

Varity_R

0.30

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over