chr3-113400632-C-A

Position:

• chr3-113400632-C-A

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.Glu463Ter) 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:3
• 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]

LOC127898559 (HGNC:):

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/exons	MANE	UniProt
CFAP44	NM_001164496.2	c.1387G>T	p.Glu463Ter	stop_gained	12/35	ENST00000393845.9
LOC127898559	NR_183046.1	n.4668G>T		non_coding_transcript_exon_variant	29/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP44	ENST00000393845.9	c.1387G>T	p.Glu463Ter	stop_gained	12/35	5	NM_001164496.2	P2
CFAP44	ENST00000295868.6	c.1387G>T	p.Glu463Ter	stop_gained	12/21	1		A2
CFAP44	ENST00000465186.1	c.*35G>T		3_prime_UTR_variant, NMD_transcript_variant	3/4	5
CFAP44	ENST00000488854.6	c.*803G>T		3_prime_UTR_variant, NMD_transcript_variant	9/16	5

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 20 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics, First Genomix Laboratory	Jul 04, 2022	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). -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 02, 2018	- -

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
MutationTaster	Benign	1.0	A;A
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;