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GeneBe

rs749163856

chr12-121921424-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_144668.6(CFAP251):c.123del(p.Asp42MetfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CFAP251
NM_144668.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: -0.0150
Variant links:
Genes affected
CFAP251 (HGNC:28506): (cilia and flagella associated protein 251) This protein encoded by this gene belongs to the WD repeat-containing family of proteins, which function in the formation of protein-protein complexes in a variety of biological pathways. This family member appears to function in the determination of mean platelet volume (MPV), and polymorphisms in this gene have been associated with variance in MPV. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2011]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-121921424-CA-C is Pathogenic according to our data. Variant chr12-121921424-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 548450.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFAP251NM_144668.6 linkuse as main transcriptc.123del p.Asp42MetfsTer4 frameshift_variant 2/22 ENST00000288912.9
CFAP251NM_001178003.2 linkuse as main transcriptc.123del p.Asp42MetfsTer4 frameshift_variant 2/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFAP251ENST00000288912.9 linkuse as main transcriptc.123del p.Asp42MetfsTer4 frameshift_variant 2/221 NM_144668.6 Q8TBY9-1
CFAP251ENST00000397454.2 linkuse as main transcriptc.123del p.Asp42MetfsTer4 frameshift_variant 2/181 P1Q8TBY9-2
CFAP251ENST00000540779.1 linkuse as main transcriptn.21del non_coding_transcript_exon_variant 1/32

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000803
AC:
2
AN:
249042
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135238
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 SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461790
Hom.:
0
Cov.:
53
AF XY:
0.00000413
AC XY:
3
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Spermatogenic failure 33 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 04, 2024- -
Non-syndromic male infertility due to sperm motility disorder;C4706677:Male infertility with teratozoospermia due to single gene mutation Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingMarseille Medical Genetics, U1251, Aix Marseille University, InsermJun 29, 2018Bialleleic rare loss-of-function variants in WDR66 have been described in two independent cases of asthenozoospermia with multiple morphologic abnormalities of the sperm flagellum. In one of these cases the p.Asp42Metfs*4 variant is homozygous in two affected brothers but heterozygous or absent in two unaffected brothers in a consanguineous family. The mitochondrial sheath was not studied in this case. In the second case, there is compound heterozygozity for p.Leu530Valfs*4 and p.Glu111*. In this second case a dysplasia of the mitochondrial sheath was described by immunofluorescence and electron microscopy (Auguste et al. 2018, article in revision). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749163856; hg19: chr12-122359330; API