X-13746411-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003611.3(OFD1):​c.610A>G​(p.Lys204Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Consequence

OFD1
NM_003611.3 missense

Scores

2
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OFD1NM_003611.3 linkuse as main transcriptc.610A>G p.Lys204Glu missense_variant 7/23 ENST00000340096.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OFD1ENST00000340096.11 linkuse as main transcriptc.610A>G p.Lys204Glu missense_variant 7/231 NM_003611.3 P1O75665-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 25, 2019In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a OFD1-related disease. This sequence change replaces lysine with glutamic acid at codon 204 of the OFD1 protein (p.Lys204Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;.;.;T
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Uncertain
0.59
D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.7
M;.;M;.
MutationTaster
Benign
0.84
N;N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.2
N;N;N;.
REVEL
Uncertain
0.43
Sift
Uncertain
0.0080
D;T;T;.
Sift4G
Benign
0.24
T;T;T;T
Polyphen
1.0
D;D;D;.
Vest4
0.27
MutPred
0.23
Loss of ubiquitination at K204 (P = 0.0161);.;Loss of ubiquitination at K204 (P = 0.0161);.;
MVP
0.95
MPC
0.61
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.65
gMVP
0.41

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.

Other links and lift over

dbSNP: rs1060500183; hg19: chrX-13764530; API