4-2462603-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001193282.4(CFAP99):c.1822C>G(p.Arg608Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,405,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CFAP99
NM_001193282.4 missense, splice_region

Scores

Splicing: ADA: 0.002532

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.517

Variant links:

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]

CFAP99 links:

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]

RNF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.083391935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP99	XM_047415685.1 link	c.1822C>G	p.Arg608Gly	missense_variant	Exon 15 of 15		XP_047271641.1
CFAP99	NM_001193282.4 link	c.1822C>G	p.Arg608Gly	missense_variant, splice_region_variant	Exon 15 of 16		NP_001180211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
CFAP99	ENST00000635017.1 link	c.1822C>G	p.Arg608Gly	missense_variant	Exon 15 of 15	5	ENSP00000488922.2	D6REC4
CFAP99	ENST00000506607.2 link	c.367C>G	p.Arg123Gly	missense_variant, splice_region_variant	Exon 2 of 3	5		A0A499FIZ3
RNF4	ENST00000503659.5 link	c.-160C>G		splice_region_variant	Exon 1 of 3	4	ENSP00000423186.1
RNF4	ENST00000503659.5 link	c.-160C>G		5_prime_UTR_variant	Exon 1 of 3	4	ENSP00000423186.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1253846

Hom.:

Cov.:

AF XY:

0.0000260

AC XY:

AN XY:

614756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000373

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000591

Gnomad4 OTH exome

AF:

0.0000389

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1822C>G (p.R608G) alteration is located in exon 15 (coding exon 14) of the CFAP99 gene. This alteration results from a C to G substitution at nucleotide position 1822, causing the arginine (R) at amino acid position 608 to be replaced by a glycine (G). 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

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.85

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.42

T;T;T

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.083

T;T;T

MetaSVM

Benign

-1.0

REVEL

Benign

0.044

Sift4G

Benign

0.14

T;D;.

Vest4

0.11

MVP

0.25

ClinPred

0.085

GERP RS

1.6

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over