NM_003611.3:c.2168C>T

Variant names:

• chrX-13760628-C-T
• rs746300545
• NM_003611.3:c.2168C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_003611.3(OFD1):​c.2168C>T​(p.Ser723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,209,651 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S723S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom. 4 hem.)
• Consequence: OFD1 NM_003611.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.06
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24747637).
• BP6: Variant X-13760628-C-T is Benign according to our data. Variant chrX-13760628-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194632.
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.2168C>T	p.Ser723Leu	missense	Exon 16 of 23	NP_003602.1
	OFD1	NM_001440947.1		c.2168C>T	p.Ser723Leu	missense	Exon 16 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.2048C>T	p.Ser683Leu	missense	Exon 15 of 22	NP_001317138.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.2168C>T	p.Ser723Leu	missense	Exon 16 of 23	ENSP00000344314.6
	OFD1	ENST00000380550.6	TSL:1	c.2048C>T	p.Ser683Leu	missense	Exon 15 of 22	ENSP00000369923.3
	OFD1	ENST00000922714.1		c.2171C>T	p.Ser724Leu	missense	Exon 16 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111884 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000651

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000330 AC: 6 AN: 181859 AF XY: 0.00

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1097767 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363131

African (AFR) AF: 0.0000758 AC: 2 AN: 26394

American (AMR) AF: 0.0000568 AC: 2 AN: 35185

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54091

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841801

Other (OTH) AF: 0.00 AC: 0 AN: 46077

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111884 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34058

African (AFR) AF: 0.0000651 AC: 2 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 10657

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53100

Other (OTH) AF: 0.00 AC: 0 AN: 1492

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome;C1510460:Orofaciodigital syndrome I (1)
-	1	-	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	7.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.31
Sift	Benign	0.067	T
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.12
MutPred		0.21		Loss of phosphorylation at S723 (P = 0.0118)
MVP		0.90
MPC		0.48
ClinPred		0.16	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.37
Mutation Taster		=90/10	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: rs746300545; hg19: chrX-13778747;