rs373792491

Positions:

• chrX-13758428-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP3 BP6 BS2_Supporting

The NM_003611.3(OFD1):​c.1634A>G​(p.Gln545Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000411 in 1,168,999 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000040 (0 hom. 17 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.86

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 -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• BP6: Variant X-13758428-A-G is Benign according to our data. Variant chrX-13758428-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447888.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OFD1	NM_003611.3	c.1634A>G	p.Gln545Arg	missense_variant	15/23	ENST00000340096.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OFD1	ENST00000340096.11	c.1634A>G	p.Gln545Arg	missense_variant	15/23	1	NM_003611.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000536 AC: 6 AN: 111894 Hom.: 0 Cov.: 22 AF XY: 0.0000587 AC XY: 2 AN XY: 34064

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000493 AC: 9 AN: 182633 Hom.: 0 AF XY: 0.0000446 AC XY: 3 AN XY: 67215

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.000536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 42 AN: 1057105 Hom.: 0 Cov.: 25 AF XY: 0.0000522 AC XY: 17 AN XY: 325931

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000569

Gnomad4 ASJ exome AF: 0.000680

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000298

Gnomad4 OTH exome AF: 0.0000670

GnomAD4 genome AF: 0.0000536 AC: 6 AN: 111894 Hom.: 0 Cov.: 22 AF XY: 0.0000587 AC XY: 2 AN XY: 34064

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000950

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 04, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2020

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.011	D;D;T
Sift4G	Uncertain	0.046	D;T;T
Polyphen		1.0	D;D;D
Vest4		0.62
MVP		0.99
MPC		0.56
ClinPred		0.30	T
GERP RS		5.6
Varity_R		0.33
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

Other links and lift over

dbSNP: rs373792491; hg19: chrX-13776547;