rs61746932

Positions:

chrX-13756620-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003611.3(OFD1):c.1264A>G(p.Lys422Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,204,450 control chromosomes in the GnomAD database, including 12 homozygotes. There are 317 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., 173 hem., cov: 22)

Exomes 𝑓: 0.00055 ( 6 hom. 144 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.15

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061338246).

BP6

Variant X-13756620-A-G is Benign according to our data. Variant chrX-13756620-A-G is described in ClinVar as [Benign]. Clinvar id is 159464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-13756620-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0054 (607/112378) while in subpopulation AFR AF= 0.0187 (578/30914). AF 95% confidence interval is 0.0174. There are 6 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OFD1	NM_003611.3 linkuse as main transcript	c.1264A>G	p.Lys422Glu	missense_variant	13/23	ENST00000340096.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OFD1	ENST00000340096.11 linkuse as main transcript	c.1264A>G	p.Lys422Glu	missense_variant	13/23	1	NM_003611.3	P1	O75665-1

Frequencies

GnomAD3 genomes

AF:

0.00540

AC:

607

AN:

112325

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

174

AN XY:

34475

show subpopulations

Gnomad AFR

AF:

0.0187

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00179

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:

0.00

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00166

AC:

295

AN:

177743

Hom.:

AF XY:

0.00125

AC XY:

AN XY:

63249

show subpopulations

Gnomad AFR exome

AF:

0.0206

Gnomad AMR exome

AF:

0.000991

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:

0.00

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.000547

AC:

597

AN:

1092072

Hom.:

Cov.:

AF XY:

0.000402

AC XY:

144

AN XY:

358606

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.00110

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:

0.0000107

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.00540

AC:

607

AN:

112378

Hom.:

Cov.:

AF XY:

0.00501

AC XY:

173

AN XY:

34538

show subpopulations

Gnomad4 AFR

AF:

0.0187

Gnomad4 AMR

AF:

0.00178

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00661

Alfa

AF:

0.00215

Hom.:

Bravo

AF:

0.00648

ESP6500AA

AF:

0.0214

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00188

AC:

228

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 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

May 10, 2018

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. -

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

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;.;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.69

T;T;T;T

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.7

L;.;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.5

N;N;N;.

REVEL

Benign

0.25

Sift

Benign

0.077

T;T;D;.

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.25

B;B;B;.

Vest4

0.17

MVP

0.87

MPC

0.25

ClinPred

0.015

GERP RS

0.66

Varity_R

0.16

gMVP

0.14

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

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