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GeneBe

4-2462457-A-C

Variant summary

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

The NM_001193282.4(CFAP99):c.1676A>C(p.Lys559Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,462,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 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. K559E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

CFAP99
NM_001193282.4 missense

Scores

1
1
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05
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]
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]

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=0.08928138).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFAP99NM_001193282.4 linkuse as main transcriptc.1676A>C p.Lys559Thr missense_variant 15/16 ENST00000635017.2
CFAP99XM_047415685.1 linkuse as main transcriptc.1676A>C p.Lys559Thr missense_variant 15/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFAP99ENST00000635017.2 linkuse as main transcriptc.1676A>C p.Lys559Thr missense_variant 15/165 NM_001193282.4 P1
RNF4ENST00000503659.5 linkuse as main transcriptc.-306A>C 5_prime_UTR_variant 1/34

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000970
AC:
6
AN:
61876
Hom.:
0
AF XY:
0.000138
AC XY:
5
AN XY:
36246
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000169
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000289
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000550
AC:
72
AN:
1309962
Hom.:
0
Cov.:
33
AF XY:
0.0000728
AC XY:
47
AN XY:
645320
show subpopulations
Gnomad4 AFR exome
AF:
0.0000386
Gnomad4 AMR exome
AF:
0.0000870
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000177
Gnomad4 SAS exome
AF:
0.000397
Gnomad4 FIN exome
AF:
0.0000310
Gnomad4 NFE exome
AF:
0.0000276
Gnomad4 OTH exome
AF:
0.0000735
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00103
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000756
ExAC
AF:
0.000272
AC:
4
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 17, 2022The c.1676A>C (p.K559T) alteration is located in exon 15 (coding exon 14) of the CFAP99 gene. This alteration results from a A to C substitution at nucleotide position 1676, causing the lysine (K) at amino acid position 559 to be replaced by a threonine (T). 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
-0.34
T
BayesDel_noAF
Benign
-0.43
Cadd
Benign
22
Dann
Uncertain
0.98
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.53
T;T;T
M_CAP
Pathogenic
0.30
D
MetaRNN
Benign
0.089
T;T;T
MetaSVM
Benign
-0.98
T
Sift4G
Benign
0.074
T;D;.
Vest4
0.19
MVP
0.061
ClinPred
0.32
T
GERP RS
3.4
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs561635965; hg19: chr4-2464184; API