4-2462457-A-T

Variant names:

• chr4-2462457-A-T
• rs561635965
• NM_001193282.4:c.1676A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193282.4(CFAP99):​c.1676A>T​(p.Lys559Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,462,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K559T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CFAP99 NM_001193282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21661416).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP99	NM_001193282.4	MANE Select	c.1676A>T	p.Lys559Met	missense	Exon 15 of 16	NP_001180211.2	D6REC4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP99	ENST00000635017.2	TSL:5 MANE Select	c.1676A>T	p.Lys559Met	missense	Exon 15 of 16	ENSP00000488922.2	D6REC4
	RNF4	ENST00000503659.5	TSL:4	c.-306A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000423186.1
	CFAP99	ENST00000860043.1		c.1679A>T	p.Lys560Met	missense	Exon 15 of 16	ENSP00000530102.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1309966 Hom.: 0 Cov.: 33 AF XY: 0.00000155 AC XY: 1 AN XY: 645320

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25940

American (AMR) AF: 0.00 AC: 0 AN: 22988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22358

East Asian (EAS) AF: 0.00 AC: 0 AN: 28246

South Asian (SAS) AF: 0.00 AC: 0 AN: 70572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3840

European-Non Finnish (NFE) AF: 9.53e-7 AC: 1 AN: 1049332

Other (OTH) AF: 0.00 AC: 0 AN: 54390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.97
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.0
REVEL	Benign	0.091
Sift4G	Benign	0.13	T
Vest4		0.30
MVP		0.055
ClinPred		0.91	D
GERP RS		3.4
PromoterAI		0.0040	Neutral
gMVP		0.26
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs561635965; hg19: chr4-2464184;