15-22870086-G-A

Variant names:

• chr15-22870086-G-A
• rs1226540181
• NM_014608.6:c.3704C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014608.6(CYFIP1):​c.3704C>T​(p.Pro1235Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1235S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CYFIP1 NM_014608.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

CYFIP1 (HGNC:13759): (cytoplasmic FMR1 interacting protein 1) This gene encodes a protein that regulates cytoskeletal dynamics and protein translation. The encoded protein is a component of the WAVE regulatory complex (WRC), which promotes actin polymerization. This protein also interacts with the synaptic functional regulator FMR1 protein and translation initiation factor 4E to inhibit protein translation. A large chromosomal deletion including this gene is associated with increased risk of schizophrenia and epilepsy in human patients. Reduced expression of this gene has been observed in various human cancers and the encoded protein may inhibit tumor invasion. [provided by RefSeq, Mar 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38317373).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014608.6. 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
	CYFIP1	NM_014608.6	MANE Select	c.3704C>T	p.Pro1235Leu	missense	Exon 31 of 31	NP_055423.1	Q7L576-1
	CYFIP1	NM_001324119.2		c.3806C>T	p.Pro1269Leu	missense	Exon 31 of 31	NP_001311048.1
	CYFIP1	NM_001287810.4		c.3704C>T	p.Pro1235Leu	missense	Exon 32 of 32	NP_001274739.1	Q7L576-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYFIP1	ENST00000617928.5	TSL:1 MANE Select	c.3704C>T	p.Pro1235Leu	missense	Exon 31 of 31	ENSP00000481038.1	Q7L576-1
	CYFIP1	ENST00000610365.4	TSL:1	c.3704C>T	p.Pro1235Leu	missense	Exon 32 of 32	ENSP00000478779.1	Q7L576-1
	CYFIP1	ENST00000617556.4	TSL:1	c.2411C>T	p.Pro804Leu	missense	Exon 16 of 16	ENSP00000480525.1	Q7L576-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460480 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726512

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111518

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.38	T
PhyloP100		10
Sift4G	Benign	0.077	T
Vest4		0.47
gMVP		0.90

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: rs1226540181; hg19: chr15-23002982;