12-96538444-A-T

Variant names:

• chr12-96538444-A-T
• rs541409055
• NM_001306084.2:c.1852A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001306084.2(CFAP54):​c.1852A>T​(p.Lys618*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000378 in 1,536,048 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: CFAP54 NM_001306084.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-96538444-A-T is Pathogenic according to our data. Variant chr12-96538444-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 3702596.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP54	NM_001306084.2	c.1852A>T	p.Lys618*	stop_gained	Exon 13 of 68	ENST00000524981.9	NP_001293013.1
CFAP54	NM_001367885.1	c.1852A>T	p.Lys618*	stop_gained	Exon 13 of 69		NP_001354814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP54	ENST00000524981.9	c.1852A>T	p.Lys618*	stop_gained	Exon 13 of 68	5	NM_001306084.2	ENSP00000431759.5
CFAP54	ENST00000553778.6	n.1708A>T		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000452066.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152222 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000240 AC: 33 AN: 137768 Hom.: 1 AF XY: 0.000308 AC XY: 23 AN XY: 74726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000473

GnomAD4 exome AF: 0.000400 AC: 554 AN: 1383708 Hom.: 1 Cov.: 30 AF XY: 0.000401 AC XY: 274 AN XY: 682808

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.000636

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000303

Gnomad4 FIN exome AF: 0.0000884

Gnomad4 NFE exome AF: 0.000446

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152340 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74502

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000160 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys618*) in the CFAP54 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFAP54 are known to be pathogenic (PMID: 26224312, 31108397). This variant is present in population databases (rs541409055, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CFAP54-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.34
GERP RS		5.4

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

LitVar

Other links and lift over

dbSNP: rs541409055; hg19: chr12-96932222;