NM_032930.3:c.110+1G>T

Variant names:

• chr11-102047581-G-T
• rs865809219
• NM_032930.3:c.110+1G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_032930.3(CFAP300):​c.110+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000521 in 1,535,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CFAP300 NM_032930.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.89

Genes affected

CFAP300 (HGNC:28188): (cilia and flagella associated protein 300) Predicted to be located in cytoplasm and motile cilium. Implicated in primary ciliary dyskinesia 38. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.17910448 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-102047581-G-T is Pathogenic according to our data. Variant chr11-102047581-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2785963.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP300	NM_032930.3	c.110+1G>T		splice_donor_variant, intron_variant	Intron 1 of 6	ENST00000434758.7	NP_116319.2
CFAP300	NM_001363505.2	c.110+1G>T		splice_donor_variant, intron_variant	Intron 1 of 5		NP_001350434.1
CFAP300	NM_001195005.2	c.110+1G>T		splice_donor_variant, intron_variant	Intron 1 of 3		NP_001181934.1
CFAP300	XM_005271713.5	c.110+1G>T		splice_donor_variant, intron_variant	Intron 1 of 5		XP_005271770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP300	ENST00000434758.7	c.110+1G>T		splice_donor_variant, intron_variant	Intron 1 of 6	2	NM_032930.3	ENSP00000414390.2
CFAP300	ENST00000534360.1	c.110+1G>T		splice_donor_variant, intron_variant	Intron 1 of 3	1		ENSP00000435482.1
CFAP300	ENST00000530659.1	n.114G>T		non_coding_transcript_exon_variant	Exon 1 of 6	1
CFAP300	ENST00000526781.5	c.110+1G>T		splice_donor_variant, intron_variant	Intron 1 of 5	3		ENSP00000433074.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000964

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

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1383418 Hom.: 0 Cov.: 30 AF XY: 0.00000293 AC XY: 2 AN XY: 682704

Gnomad4 AFR exome AF: 0.000127

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: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74384

Gnomad4 AFR AF: 0.0000964

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

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 1 of the C11orf70 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in C11orf70 are known to be pathogenic (PMID: 29727692, 29727693). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with C11orf70-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.86	D
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs865809219; hg19: chr11-101918312;