Variant 12-121921424-CA-C details in Genebe, Genetics Data Aggregator

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]

CFAP251 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

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	Protein	UniProt
CFAP251	NM_144668.6 linkuse as main transcript	c.123del	p.Asp42MetfsTer4	frameshift_variant	2/22	ENST00000288912.9	NP_653269.3
CFAP251	NM_001178003.2 linkuse as main transcript	c.123del	p.Asp42MetfsTer4	frameshift_variant	2/18		NP_001171474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP251	ENST00000288912.9 linkuse as main transcript	c.123del	p.Asp42MetfsTer4	frameshift_variant	2/22	1	NM_144668.6	ENSP00000288912		Q8TBY9-1
CFAP251	ENST00000397454.2 linkuse as main transcript	c.123del	p.Asp42MetfsTer4	frameshift_variant	2/18	1		ENSP00000380595	P1	Q8TBY9-2
CFAP251	ENST00000540779.1 linkuse as main transcript	n.21del		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249042

Hom.:

AF XY:

0.0000148

AC XY:

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:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

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

Cov.:

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 provided

literature only

OMIM

Mar 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 provided

clinical testing

Marseille Medical Genetics, U1251, Aix Marseille University, Inserm

Jun 29, 2018

Bialleleic 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over