rs370183911

Variant names:

• chrX-13760490-A-G
• rs370183911
• NM_003611.3:c.2030A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-13760490-A-G
• chrX-13760490-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003611.3(OFD1):​c.2030A>G​(p.Glu677Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000948 in 1,054,423 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E677V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• orofaciodigital syndrome I

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 23

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Simpson-Golabi-Behmel syndrome type 2

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042134196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.2030A>G	p.Glu677Gly	missense_variant	Exon 16 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.2030A>G	p.Glu677Gly	missense_variant	Exon 16 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.48e-7 AC: 1 AN: 1054423 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 340779

African (AFR) AF: 0.00 AC: 0 AN: 24472

American (AMR) AF: 0.00 AC: 0 AN: 27574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16315

East Asian (EAS) AF: 0.00 AC: 0 AN: 29910

South Asian (SAS) AF: 0.00 AC: 0 AN: 46550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3774

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 823073

Other (OTH) AF: 0.00 AC: 0 AN: 44075

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.30
DANN	Benign	0.27
DEOGEN2	Benign	0.071	T;.;.
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	-0.94	N;.;.
PhyloP100		-0.46
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.50	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.057
MutPred		0.14		Gain of ubiquitination at K680 (P = 0.0539);.;.;
MVP		0.42
MPC		0.15
ClinPred		0.037	T
GERP RS		-6.0
Varity_R		0.031
gMVP		0.10
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs370183911; hg19: chrX-13778609;