rs886039860

Variant names:

• chrX-13744424-T-C
• rs886039860
• NM_003611.3:c.422T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-13744424-T-C
• chrX-13744424-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PVS1_Supporting BS2

The NM_001330210.2(OFD1):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000163 in 1,041,623 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: OFD1 NM_001330210.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.69

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 Likely_benign. Variant got -3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 19 codons. Genomic position: 13744477. Lost 0.021 part of the original CDS.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.422T>C	p.Met141Thr	missense_variant	Exon 6 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.422T>C	p.Met141Thr	missense_variant	Exon 6 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181673 Hom.: 0 AF XY: 0.0000302 AC XY: 2 AN XY: 66297

Gnomad AFR exome AF: 0.00

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: 0.0000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000163 AC: 17 AN: 1041623 Hom.: 0 Cov.: 23 AF XY: 0.0000185 AC XY: 6 AN XY: 324091

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: 0.0000202

Gnomad4 OTH exome AF: 0.0000227

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Mar 31, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M141T variant (also known as c.422T>C), located in coding exon 6 of the OFD1 gene, results from a T to C substitution at nucleotide position 422. The methionine at codon 141 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 141 of the OFD1 protein (p.Met141Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 1738898). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OFD1 protein function. 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	0.29
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.31	D
Sift4G	Uncertain	0.056	T
Vest4		0.49
MVP		0.84
ClinPred		0.73	D
GERP RS		5.2

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: rs886039860; hg19: chrX-13762543;