chrX-13760493-C-G

Variant names:

• chrX-13760493-C-G
• rs143954823
• NM_003611.3:c.2033C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003611.3(OFD1):​c.2033C>G​(p.Ala678Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,165,352 control chromosomes in the GnomAD database, including 1 homozygotes. There are 107 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., 48 hem., cov: 22)
  • Exomes 𝑓: 0.00025 (0 hom. 59 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.166
• Publications: 2 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):

• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• OFD1-related ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004306376).
• BP6: Variant X-13760493-C-G is Benign according to our data. Variant chrX-13760493-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00171 (191/111877) while in subpopulation AFR AF = 0.0052 (160/30789). AF 95% confidence interval is 0.00454. There are 1 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 48 XL,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003611.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.2033C>G	p.Ala678Gly	missense	Exon 16 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.2033C>G	p.Ala678Gly	missense	Exon 16 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.1913C>G	p.Ala638Gly	missense	Exon 15 of 22	NP_001317138.1	O75665-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.2033C>G	p.Ala678Gly	missense	Exon 16 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.1913C>G	p.Ala638Gly	missense	Exon 15 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.2036C>G	p.Ala679Gly	missense	Exon 16 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 192 AN: 111824 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00226

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: 0.0000376

Gnomad OTH AF: 0.00338

GnomAD2 exomes AF: 0.000646 AC: 93 AN: 143854 AF XY: 0.000376

Gnomad AFR exome AF: 0.00626

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.000598

GnomAD4 exome AF: 0.000246 AC: 259 AN: 1053475 Hom.: 0 Cov.: 31 AF XY: 0.000173 AC XY: 59 AN XY: 340447

African (AFR) AF: 0.00766 AC: 187 AN: 24409

American (AMR) AF: 0.000952 AC: 26 AN: 27316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16304

East Asian (EAS) AF: 0.00 AC: 0 AN: 29897

South Asian (SAS) AF: 0.0000860 AC: 4 AN: 46510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38677

Middle Eastern (MID) AF: 0.00106 AC: 4 AN: 3782

European-Non Finnish (NFE) AF: 0.0000146 AC: 12 AN: 822549

Other (OTH) AF: 0.000590 AC: 26 AN: 44031

GnomAD4 genome AF: 0.00171 AC: 191 AN: 111877 Hom.: 1 Cov.: 22 AF XY: 0.00141 AC XY: 48 AN XY: 34047

African (AFR) AF: 0.00520 AC: 160 AN: 30789

American (AMR) AF: 0.00226 AC: 24 AN: 10616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6033

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53152

Other (OTH) AF: 0.00334 AC: 5 AN: 1498

Alfa AF: 0.00142 Hom.: 3

Bravo AF: 0.00249

ESP6500AA AF: 0.00548 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000514 AC: 62

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.2
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0043	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.17
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.32	T
Sift4G	Benign	0.47	T
Polyphen		0.37	B
Vest4		0.21
MVP		0.82
MPC		0.20
ClinPred		0.0041	T
GERP RS		2.3
Varity_R		0.080
gMVP		0.15
Mutation Taster		=99/1	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: rs143954823; hg19: chrX-13778612;