10-104152728-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PP3_StrongPP5

The NM_025145.7(CFAP43):​c.3541-2A>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

CFAP43
NM_025145.7 splice_acceptor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 6.45
Variant links:
Genes affected
CFAP43 (HGNC:26684): (cilia and flagella associated protein 43) This gene encodes a member of the cilia- and flagella-associated protein family. [provided by RefSeq, Sep 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023809524 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of 7, new splice context is: gttttccttttcgtcattAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 10-104152728-T-G is Pathogenic according to our data. Variant chr10-104152728-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 523145.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-104152728-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFAP43NM_025145.7 linkuse as main transcriptc.3541-2A>C splice_acceptor_variant ENST00000357060.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFAP43ENST00000357060.8 linkuse as main transcriptc.3541-2A>C splice_acceptor_variant 1 NM_025145.7 P1Q8NDM7-1
CFAP43ENST00000434629.5 linkuse as main transcriptc.1623-2A>C splice_acceptor_variant 1
CFAP43ENST00000457071.5 linkuse as main transcriptc.87-2A>C splice_acceptor_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Spermatogenic failure 19 Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Strasbourg University HospitalFeb 09, 2021Homozygous splice site variant "c.3541-2A>C" was reported before in 2 unrelated Tunisian patients for sperm flagella problems (Coutton et al 2018, doi.org/10.1038/s41467-017-02792-7). Our patient is a Moroccan man suffering infertility due to a sperm flagellar problem. -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 02, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
D;D
GERP RS
5.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.99
Position offset: -9
DS_AL_spliceai
1.0
Position offset: -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.

Other links and lift over

dbSNP: rs1554862953; hg19: chr10-105912486; API