dbSNP rs778222701: CFAP410:c.545+1G>C (chr21-44331842-C-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004928.3(CFAP410):c.545+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. 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 (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CFAP410
NM_004928.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.79

Publications

0 publications found

Variant links:

Genes affected

CFAP410 (HGNC:1260): (cilia and flagella associated protein 410) Four alternatively spliced transcript variants encoding four different isoforms have been found for this nuclear gene. All isoforms contain leucine-rich repeats. Three of these isoforms are mitochondrial proteins and one of them lacks the target peptide, so is not located in mitochondrion. This gene is down-regulated in Down syndrome (DS) brain, which may represent mitochondrial dysfunction in DS patients. [provided by RefSeq, Sep 2012]

CFAP410 Gene-Disease associations (from GenCC):

axial spondylometaphyseal dysplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
amyotrophic lateral sclerosis
Inheritance: AD, SD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CFAP410 links:

ENSG00000184441 (HGNC:):

ENSG00000184441 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-44331842-C-G is Pathogenic according to our data. Variant chr21-44331842-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1512365.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004928.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFAP410	NM_004928.3	MANE Select	c.545+1G>C	splice_donor intron	N/A	NP_004919.1	O43822-1
CFAP410	NM_001271441.2		c.545+1G>C	splice_donor intron	N/A	NP_001258370.1	O43822-4
CFAP410	NM_001271440.2		c.545+1G>C	splice_donor intron	N/A	NP_001258369.1	O43822-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFAP410	ENST00000339818.9	TSL:1 MANE Select	c.545+1G>C	splice_donor intron	N/A	ENSP00000344566.4	O43822-1
CFAP410	ENST00000397956.7	TSL:1	c.545+1G>C	splice_donor intron	N/A	ENSP00000381047.3	O43822-4
CFAP410	ENST00000325223.7	TSL:1	c.545+1G>C	splice_donor intron	N/A	ENSP00000317302.7	O43822-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Benign

0.95

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.58

PhyloP100

2.8

GERP RS

4.6

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.92

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over