Variant 2-219014044-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_194302.4(CFAP65):c.3603G>A(p.Trp1201Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000962 in 1,455,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CFAP65
NM_194302.4 stop_gained, splice_region

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.77

Variant links:

Genes affected

CFAP65 (HGNC:25325): (cilia and flagella associated protein 65) The protein encoded by this gene has putative coiled-coil domains and may be a transmembrane protein. The chicken ortholog of this gene is involved in the Rose-comb mutation, which is a large chromosome inversion, resulting in altered comb morphology and defects in sperm motility. [provided by RefSeq, Aug 2016]

CFAP65 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 2-219014044-C-T is Pathogenic according to our data. Variant chr2-219014044-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2629507.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP65	NM_194302.4 linkuse as main transcript	c.3603G>A	p.Trp1201Ter	stop_gained, splice_region_variant	22/35	ENST00000341552.10	NP_919278.2
LOC100129175	NR_046086.1 linkuse as main transcript	n.315C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP65	ENST00000341552.10 linkuse as main transcript	c.3603G>A	p.Trp1201Ter	stop_gained, splice_region_variant	22/35	5	NM_194302.4	ENSP00000340776	A2	Q6ZU64-1
	ENST00000441450.1 linkuse as main transcript	n.315C>T		non_coding_transcript_exon_variant	3/3	2
CFAP65	ENST00000453220.5 linkuse as main transcript	c.3603G>A	p.Trp1201Ter	stop_gained, splice_region_variant	20/33	5		ENSP00000409117	A2	Q6ZU64-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152066

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245264

Hom.:

AF XY:

0.00000754

AC XY:

AN XY:

132638

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:

0.0000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000962

AC:

AN:

1455108

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

722952

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:

0.000164

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CFAP65-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2023

The CFAP65 c.3603G>A variant is predicted to result in premature protein termination (p.Trp1201*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0034% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219878766-C-T). Nonsense variants in CFAP65 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

0.55

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.067

MutationTaster

Benign

1.0

A;A;A

Vest4

0.21

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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