chr4-2462918-G-T

Variant names:

• chr4-2462918-G-T
• rs1578487267
• NM_001193282.4:c.1933G>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.1933G>T​(p.Ala645Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 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. A645T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFAP99 NM_001193282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.385
• 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]

LOC105374353 (HGNC:):

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=0.19877037).

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.1933G>T	p.Ala645Ser	missense	Exon 16 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.1933G>T	p.Ala645Ser	missense	Exon 16 of 16	ENSP00000488922.2	D6REC4
	CFAP99	ENST00000860043.1		c.1936G>T	p.Ala646Ser	missense	Exon 16 of 16	ENSP00000530102.1
	RNF4	ENST00000503659.5	TSL:4	c.-158+313G>T		intron	N/A	ENSP00000423186.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151846 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1145554 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 555612

African (AFR) AF: 0.00 AC: 0 AN: 22882

American (AMR) AF: 0.00 AC: 0 AN: 8472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14712

East Asian (EAS) AF: 0.00 AC: 0 AN: 25904

South Asian (SAS) AF: 0.00 AC: 0 AN: 37832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3064

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 961796

Other (OTH) AF: 0.00 AC: 0 AN: 45828

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151846 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74182

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15254

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67904

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000291 AC: 1 AN: 3454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.70	T
PhyloP100		0.39
Sift4G	Pathogenic	0.0	D
Vest4		0.15
MVP		0.076
ClinPred		0.14	T
GERP RS		1.9
gMVP		0.20
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1578487267; hg19: chr4-2464645;