4-2445205-C-T

Position:

• chr4-2445205-C-T

Variant summary

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

The NM_001193282.4(CFAP99):​c.539C>T​(p.Thr180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,309,600 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CFAP99 NM_001193282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.517

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=0.07954273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP99	NM_001193282.4	c.539C>T	p.Thr180Ile	missense_variant	6/16	ENST00000635017.2
CFAP99	XM_047415685.1	c.539C>T	p.Thr180Ile	missense_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP99	ENST00000635017.2	c.539C>T	p.Thr180Ile	missense_variant	6/16	5	NM_001193282.4	P1
CFAP99	ENST00000511731.5	n.419+1963C>T		intron_variant, non_coding_transcript_variant		1
CFAP99	ENST00000514556.5	n.121C>T		non_coding_transcript_exon_variant	2/4	5
CFAP99	ENST00000515732.1	n.103C>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1309600 Hom.: 0 Cov.: 30 AF XY: 0.00000155 AC XY: 1 AN XY: 643880

Gnomad4 AFR exome AF: 0.00

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: 9.60e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.539C>T (p.T180I) alteration is located in exon 6 (coding exon 5) of the CFAP99 gene. This alteration results from a C to T substitution at nucleotide position 539, causing the threonine (T) at amino acid position 180 to be replaced by an isoleucine (I). 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	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.88
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.080	T;T
Sift4G	Benign	0.26	T;T
Vest4		0.048
MVP		0.44
GERP RS		2.5
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs988050564; hg19: chr4-2446932;