4-2462898-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001193282.4(CFAP99):c.1913G>A(p.Gly638Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,324,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

CFAP99
NM_001193282.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.247

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:

LOC105374353 (HGNC:):

LOC105374353 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059713572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
CFAP99	NM_001193282.4 link	c.1913G>A	p.Gly638Glu	missense_variant	Exon 16 of 16	NP_001180211.2
CFAP99	XM_047415685.1 link	c.2117G>A	p.Gly706Glu	missense_variant	Exon 15 of 15	XP_047271641.1
LOC105374353	XR_007057992.1 link	n.-106G>A		upstream_gene_variant
LOC105374353	XR_925057.3 link	n.-111G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
CFAP99	ENST00000635017.1 link	c.2117G>A	p.Gly706Glu	missense_variant	Exon 15 of 15	5	ENSP00000488922.2	D6REC4
CFAP99	ENST00000506607.2 link	c.458G>A	p.Gly153Glu	missense_variant	Exon 3 of 3	5		A0A499FIZ3
RNF4	ENST00000503659.5 link	c.-158+293G>A		intron_variant	Intron 1 of 2	4	ENSP00000423186.1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000324

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

14996

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

9504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000637

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000201

AC:

236

AN:

1172394

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

113

AN XY:

571402

show subpopulations

Gnomad4 AFR exome

AF:

0.0000427

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:

0.000236

Gnomad4 OTH exome

AF:

0.000106

GnomAD4 genome

AF:

0.000158

AC:

AN:

151858

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000324

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000990

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1913G>A (p.G638E) alteration is located in exon 16 (coding exon 15) of the CFAP99 gene. This alteration results from a G to A substitution at nucleotide position 1913, causing the glycine (G) at amino acid position 638 to be replaced by a glutamic acid (E). 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

-0.48

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.47

T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-0.97

REVEL

Benign

0.015

Sift4G

Pathogenic

0.0

D;T;.

Vest4

0.10

MVP

0.099

ClinPred

0.023

GERP RS

-0.26

gMVP

0.072

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

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