dbSNP rs5979959: OFD1:p.Glu340Glu (chrX-13751333-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003611.3(OFD1):c.1020G>A(p.Glu340Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,199,911 control chromosomes in the GnomAD database, including 9 homozygotes. There are 344 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 6 hom., 161 hem., cov: 23)

Exomes 𝑓: 0.00060 ( 3 hom. 183 hem. )

Consequence

OFD1
NM_003611.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.480

Publications

3 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae)
OFD1-related ciliopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
orofaciodigital syndrome I
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
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

OFD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant X-13751333-G-A is Benign according to our data. Variant chrX-13751333-G-A is described in ClinVar as Benign. ClinVar VariationId is 159463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.48 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00583 (652/111888) while in subpopulation AFR AF = 0.0199 (612/30797). AF 95% confidence interval is 0.0186. There are 6 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OFD1	NM_003611.3	MANE Select	c.1020G>A	p.Glu340Glu	synonymous	Exon 10 of 23	NP_003602.1	O75665-1
OFD1	NM_001440947.1		c.1020G>A	p.Glu340Glu	synonymous	Exon 10 of 22	NP_001427876.1
OFD1	NM_001330210.2		c.600G>A	p.Glu200Glu	synonymous	Exon 11 of 24	NP_001317139.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OFD1	ENST00000340096.11	TSL:1 MANE Select	c.1020G>A	p.Glu340Glu	synonymous	Exon 10 of 23	ENSP00000344314.6	O75665-1
OFD1	ENST00000380550.6	TSL:1	c.935+1800G>A		intron	N/A	ENSP00000369923.3	O75665-3
OFD1	ENST00000922714.1		c.1023G>A	p.Glu341Glu	synonymous	Exon 10 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes

AF:

0.00583

AC:

652

AN:

111836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0199

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00237

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00667

GnomAD2 exomes

AF:

0.00169

AC:

307

AN:

181861

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.000553

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000613

Gnomad OTH exome

AF:

0.000892

GnomAD4 exome

AF:

0.000601

AC:

654

AN:

1088023

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

183

AN XY:

353987

show subpopulations

African (AFR)

AF:

0.0208

AC:

545

AN:

26158

American (AMR)

AF:

0.00106

AC:

AN:

34988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19280

East Asian (EAS)

AF:

0.00

AC:

AN:

30134

South Asian (SAS)

AF:

0.00

AC:

AN:

53297

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

833867

Other (OTH)

AF:

0.00138

AC:

AN:

45739

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00583

AC:

652

AN:

111888

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

161

AN XY:

34074

show subpopulations

African (AFR)

AF:

0.0199

AC:

612

AN:

30797

American (AMR)

AF:

0.00237

AC:

AN:

10559

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3596

South Asian (SAS)

AF:

0.00

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5962

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

53222

Other (OTH)

AF:

0.00659

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00344

Hom.:

Bravo

AF:

0.00726

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Joubert syndrome;C1510460:Orofaciodigital syndrome I (1)

not provided (1)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.2

(source)

DANN

Benign

0.57

PhyloP100

0.48

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over