X-13735079-C-A

Variant names:

• chrX-13735079-C-A
• rs750315398
• NM_003611.3:c.8C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003611.3(OFD1):​c.8C>A​(p.Ala3Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,197,409 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.678

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31801242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112366 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34526

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085043 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 1 AN XY: 356305

Gnomad4 AFR exome AF: 0.00

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: 0.00000239

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112366 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34526

Gnomad4 AFR AF: 0.00

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: 0.0000188

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8C>A (p.A3E) alteration is located in exon 1 (coding exon 1) of the OFD1 gene. This alteration results from a C to A substitution at nucleotide position 8, causing the alanine (A) at amino acid position 3 to be replaced by a glutamic acid (E). 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

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 3 of the OFD1 protein (p.Ala3Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OFD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2475764). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T;.
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.55	T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.39	N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.26
MutPred		0.095		Gain of disorder (P = 0.0706);Gain of disorder (P = 0.0706);
MVP		0.76
MPC		0.46
ClinPred		0.64	D
GERP RS		2.9
Varity_R		0.088
gMVP		0.52

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

Other links and lift over

dbSNP: rs750315398; hg19: chrX-13753198;