rs370183911

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003611.3(OFD1):c.2030A>T(p.Glu677Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,166,428 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

OFD1
NM_003611.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.459

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1161547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OFD1	NM_003611.3 linkuse as main transcript	c.2030A>T	p.Glu677Val	missense_variant	16/23	ENST00000340096.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OFD1	ENST00000340096.11 linkuse as main transcript	c.2030A>T	p.Glu677Val	missense_variant	16/23	1	NM_003611.3	P1	O75665-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34159

show subpopulations

Gnomad AFR

AF:

0.0000975

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000690

AC:

AN:

144889

Hom.:

AF XY:

0.00

AC XY:

AN XY:

48101

show subpopulations

Gnomad AFR exome

AF:

0.0000811

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000190

AC:

AN:

1054423

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

340779

show subpopulations

Gnomad4 AFR exome

AF:

0.0000817

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34159

show subpopulations

Gnomad4 AFR

AF:

0.0000975

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.2030A>T (p.E677V) alteration is located in exon 16 (coding exon 16) of the OFD1 gene. This alteration results from a A to T substitution at nucleotide position 2030, causing the glutamic acid (E) at amino acid position 677 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 11, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 404260). This variant has not been reported in the literature in individuals affected with OFD1-related conditions. This variant is present in population databases (rs370183911, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 677 of the OFD1 protein (p.Glu677Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.30

Cadd

Benign

7.2

Dann

Benign

0.90

DEOGEN2

Benign

0.15

T;.;.

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.67

T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Uncertain

-0.039

MutationAssessor

Benign

0.90

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.59

P;B;B

Vest4

0.24

MVP

0.83

MPC

0.23

ClinPred

0.050

GERP RS

-6.0

Varity_R

0.11

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 25

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