rs866096259

Variant names:

• chr3-113400632-C-A
• rs866096259
• NM_001164496.2:c.1387G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-113400632-C-A
• chr3-113400632-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001164496.2(CFAP44):​c.1387G>T​(p.Glu463*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000343 in 1,458,894 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CFAP44 NM_001164496.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.04

Genes affected

CFAP44 (HGNC:25631): (cilia and flagella associated protein 44) Enables peptidase activity. Involved in sperm axoneme assembly. Acts upstream of or within microtubule cytoskeleton organization. Predicted to be located in cytoplasm; cytoskeleton; and motile cilium. Implicated in spermatogenic failure 20. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285943 (HGNC:58084):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 3-113400632-C-A is Pathogenic according to our data. Variant chr3-113400632-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 523152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-113400632-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP44	NM_001164496.2	c.1387G>T	p.Glu463*	stop_gained	Exon 12 of 35	ENST00000393845.9	NP_001157968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP44	ENST00000393845.9	c.1387G>T	p.Glu463*	stop_gained	Exon 12 of 35	5	NM_001164496.2	ENSP00000377428.2
ENSG00000285943	ENST00000649772.1	n.*1488G>T		non_coding_transcript_exon_variant	Exon 30 of 39			ENSP00000497606.1
ENSG00000285943	ENST00000649772.1	n.*1488G>T		3_prime_UTR_variant	Exon 30 of 39			ENSP00000497606.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458894 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 725692

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 20 Pathogenic:3

May 02, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 04, 2022

First Genomix Gene Laboratory, Genetic Diagnostics Department

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

First Genomix Laboratory has identified this variant in a homozygous state in a patient presenting with immotile sperm and Glucose-6-Phosphate Dehydrogenase Deficiency. In addition, this variant was identified in a heterozygous state in an unaffected patient. Coutton et al., 2018 have identified this variant in a homozygous state in a patient presenting with primary infertility due to multiple morphological abnormalities of the flagella (PMID: 29449551). -

CFAP44-related disorder Pathogenic:1

Jul 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFAP44 c.1387G>T variant is predicted to result in premature protein termination (p.Glu463*). This variant has been reported in the homozygous state in two unrelated patients with primary infertility due to multiple morphologic abnormalities of sperm flagella with severe disorganization of the sperm axoneme (Coutton et al. 2018. PubMed ID: 29449551). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CFAP44 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.29
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs866096259; hg19: chr3-113119479;