Genetic Variant CFAP54:p.Arg1629Cys (chr12-96651600-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001306084.2(CFAP54):c.4885C>T(p.Arg1629Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CFAP54
NM_001306084.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.32

Publications

1 publications found

Variant links:

Genes affected

CFAP54 (HGNC:26456): (cilia and flagella associated protein 54) Predicted to be involved in cilium assembly; cilium movement involved in cell motility; and spermatogenesis. Predicted to act upstream of or within cerebrospinal fluid circulation; motile cilium assembly; and mucociliary clearance. Predicted to be located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

CFAP54 Gene-Disease associations (from GenCC):

ciliary dyskinesia, primary, 54
Inheritance: AR Classification: STRONG Submitted by: ClinGen

CFAP54 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

PP5

Variant 12-96651600-C-T is Pathogenic according to our data. Variant chr12-96651600-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3767884.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306084.2. 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
	CFAP54	NM_001306084.2	MANE Select	c.4885C>T	p.Arg1629Cys	missense	Exon 36 of 68	NP_001293013.1	Q96N23-1
	CFAP54	NM_001367885.1		c.4885C>T	p.Arg1629Cys	missense	Exon 36 of 69	NP_001354814.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFAP54	ENST00000524981.9	TSL:5 MANE Select	c.4885C>T	p.Arg1629Cys	missense	Exon 36 of 68	ENSP00000431759.5	Q96N23-1
CFAP54	ENST00000637336.1	TSL:5	c.1600C>T	p.Arg534Cys	missense	Exon 13 of 46	ENSP00000490000.1	A0A1B0GU80
CFAP54	ENST00000342887.1	TSL:2	n.238C>T		non_coding_transcript_exon	Exon 3 of 27

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251234

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111874

Other (OTH)

AF:

0.0000497

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spermatogenic failure 98 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

-0.11

PhyloP100

5.3

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Vest4

0.76

MVP

0.42

MPC

0.29

ClinPred

0.99

GERP RS

4.9

Varity_R

0.50

gMVP

0.42

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over