4-2462498-C-A

Variant names:

• chr4-2462498-C-A
• rs926921257
• ENST00000635017.1:c.1717C>A

Variant summary

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

The NM_001193282.4(CFAP99):​c.1717C>A​(p.Arg573Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,325,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CFAP99 NM_001193282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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]

RNF4 (HGNC:10067): (ring finger protein 4) The protein encoded by this gene contains a RING finger motif and acts as a transcription regulator. This protein has been shown to interact with, and inhibit the activity of, TRPS1, a transcription suppressor of GATA-mediated transcription. Transcription repressor ZNF278/PATZ is found to interact with this protein, and thus reduce the enhancement of androgen receptor-dependent transcription mediated by this protein. Studies of the mouse and rat counterparts suggested a role of this protein in spermatogenesis. A pseudogene of this gene is found on chromosome 1.[provided by RefSeq, Jul 2010]

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=0.24724469).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP99	NM_001193282.4	c.1717C>A	p.Arg573Ser	missense_variant	Exon 15 of 16		NP_001180211.2
CFAP99	XM_047415685.1	c.1717C>A	p.Arg573Ser	missense_variant	Exon 15 of 15		XP_047271641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP99	ENST00000635017.1	c.1717C>A	p.Arg573Ser	missense_variant	Exon 15 of 15	5		ENSP00000488922.2
CFAP99	ENST00000506607.2	c.262C>A	p.Arg88Ser	missense_variant	Exon 2 of 3	5
RNF4	ENST00000503659.5	c.-265C>A		5_prime_UTR_variant	Exon 1 of 3	4		ENSP00000423186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000131 AC: 1 AN: 76158 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 44024

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000358

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1325080 Hom.: 0 Cov.: 33 AF XY: 0.00000306 AC XY: 2 AN XY: 653240

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: 0.0000136

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.48e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1717C>A (p.R573S) alteration is located in exon 15 (coding exon 14) of the CFAP99 gene. This alteration results from a C to A substitution at nucleotide position 1717, causing the arginine (R) at amino acid position 573 to be replaced by a serine (S). 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	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.024
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.89	T
REVEL	Benign	0.17
Sift4G	Pathogenic	0.0	D;D;.
Vest4		0.41
MVP		0.11
ClinPred		0.93	D
GERP RS		3.4
gMVP		0.14

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: rs926921257; hg19: chr4-2464225;