15-22870098-C-T

Variant names:

• chr15-22870098-C-T
• rs1289296912
• NM_014608.6:c.3692G>A

Variant summary

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

The NM_014608.6(CYFIP1):​c.3692G>A​(p.Gly1231Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CYFIP1 NM_014608.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3692G>A	p.Gly1231Glu	missense	Exon 31 of 31	NP_055423.1	Q7L576-1
	CYFIP1	NM_001324119.2		c.3794G>A	p.Gly1265Glu	missense	Exon 31 of 31	NP_001311048.1
	CYFIP1	NM_001287810.4		c.3692G>A	p.Gly1231Glu	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.3692G>A	p.Gly1231Glu	missense	Exon 31 of 31	ENSP00000481038.1	Q7L576-1
	CYFIP1	ENST00000610365.4	TSL:1	c.3692G>A	p.Gly1231Glu	missense	Exon 32 of 32	ENSP00000478779.1	Q7L576-1
	CYFIP1	ENST00000617556.4	TSL:1	c.2399G>A	p.Gly800Glu	missense	Exon 16 of 16	ENSP00000480525.1	Q7L576-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460778 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726656

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111602

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

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	0.21
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
LIST_S2	Uncertain	0.96	D
MetaRNN	Uncertain	0.64	D
PhyloP100		5.0
Sift4G	Benign	1.0	T
Vest4		0.53
gMVP		0.93
Mutation Taster		=98/2	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: rs1289296912; hg19: chr15-23002970;