10-104147999-CT-C

Variant names:

• chr10-104147999-CT-C
• rs1554861288
• NM_025145.7:c.3661-2delA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_025145.7(CFAP43):​c.3661-2delA variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 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, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.08
• Publications: 2 publications found

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]

CFAP43 Gene-Disease associations (from GenCC):

• spermatogenic failure 19

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen, Ambry Genetics
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• normal pressure hydrocephalus

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000294028 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021608643 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of -42, new splice context is: tatagaaaatattgtctcAGgtg. Cryptic site results in inframe 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
• PP5: Variant 10-104147999-CT-C is Pathogenic according to our data. Variant chr10-104147999-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 523144.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP43	NM_025145.7	c.3661-2delA		splice_acceptor_variant, intron_variant	Intron 28 of 37	ENST00000357060.8	NP_079421.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP43	ENST00000357060.8	c.3661-2delA		splice_acceptor_variant, intron_variant	Intron 28 of 37	1	NM_025145.7	ENSP00000349568.3
CFAP43	ENST00000434629.5	c.1741-2delA		splice_acceptor_variant, intron_variant	Intron 14 of 22	1		ENSP00000391364.1
CFAP43	ENST00000457071.5	c.205-2delA		splice_acceptor_variant, intron_variant	Intron 2 of 11	2		ENSP00000394274.1
ENSG00000294028	ENST00000720641.1	n.109-13994delT		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 19 Pathogenic:1

Sep 26, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554861288; hg19: chr10-105907757;