chr12-121921424-CA-C

Variant names:

• chr12-121921424-CA-C
• rs749163856
• NM_144668.6:c.123delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_144668.6(CFAP251):​c.123delA​(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
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -0.0150
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 33

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000256950 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 548450.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP251	NM_144668.6	c.123delA	p.Asp42MetfsTer4	frameshift_variant	Exon 2 of 22	ENST00000288912.9	NP_653269.3
CFAP251	NM_001178003.2	c.123delA	p.Asp42MetfsTer4	frameshift_variant	Exon 2 of 18		NP_001171474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP251	ENST00000288912.9	c.123delA	p.Asp42MetfsTer4	frameshift_variant	Exon 2 of 22	1	NM_144668.6	ENSP00000288912.4
ENSG00000256950	ENST00000546333.1	n.*228delA		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000477146.1
ENSG00000256950	ENST00000546333.1	n.*228delA		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000477146.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249042 AF XY: 0.0000148

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: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 33 Pathogenic:1

Mar 04, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Non-syndromic male infertility due to sperm motility disorder;C4706677:Male infertility with teratozoospermia due to single gene mutation Pathogenic:1

Jun 29, 2018

Marseille Medical Genetics, U1251, Aix Marseille University, Inserm

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.015
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs749163856; hg19: chr12-122359330;