4-2426497-A-G

Variant names:

• chr4-2426497-A-G
• rs1733686963
• ENST00000635017.1:c.22A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193282.4(CFAP99):​c.22A>G​(p.Ile8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I8T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFAP99 NM_001193282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190

Genes affected

CFAP99 (HGNC:51180): (cilia and flagella associated protein 99) Predicted to be located in motile cilium. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10969642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP99	NM_001193282.4	c.22A>G	p.Ile8Val	missense_variant	Exon 2 of 16		NP_001180211.2
CFAP99	XM_047415685.1	c.22A>G	p.Ile8Val	missense_variant	Exon 2 of 15		XP_047271641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP99	ENST00000635017.1	c.22A>G	p.Ile8Val	missense_variant	Exon 2 of 15	5		ENSP00000488922.2
CFAP99	ENST00000382849.2	n.159A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
CFAP99	ENST00000511731.5	n.-24A>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383752 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 682832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

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: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22A>G (p.I8V) alteration is located in exon 2 (coding exon 1) of the CFAP99 gene. This alteration results from a A to G substitution at nucleotide position 22, causing the isoleucine (I) at amino acid position 8 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.47
DANN	Benign	0.40
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.11	T;T
Sift4G	Benign	0.17	T;T
Vest4		0.16
MVP		0.099
GERP RS		0.088
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1733686963; hg19: chr4-2428224;