15-22874598-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PP3_Moderate BP6_Very_Strong BP7 BS2

The NM_014608.6(CYFIP1):c.3162C>T(p.Tyr1054=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,606,456 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (91 hom.)
• Consequence: CYFIP1 NM_014608.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.216

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

Verdict is Benign. Variant got -11 ACMG points.

• PP3: BayesDel_noAF computational evidence supports a deleterious effect, 0.5
• BP6: Variant 15-22874598-G-A is Benign according to our data. Variant chr15-22874598-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 783051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.216 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYFIP1	NM_014608.6	c.3162C>T	p.Tyr1054=	synonymous_variant	28/31	ENST00000617928.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYFIP1	ENST00000617928.5	c.3162C>T	p.Tyr1054=	synonymous_variant	28/31	1	NM_014608.6	P1

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 806 AN: 152216 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00955

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00531 AC: 1286 AN: 242018 Hom.: 8 AF XY: 0.00533 AC XY: 700 AN XY: 131352

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000407

Gnomad EAS exome AF: 0.000567

Gnomad SAS exome AF: 0.00499

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00881

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00859 AC: 12497 AN: 1454122 Hom.: 91 Cov.: 30 AF XY: 0.00837 AC XY: 6056 AN XY: 723428

Gnomad4 AFR exome AF: 0.00151

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.000810

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.00549

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00725

GnomAD4 genome AF: 0.00529 AC: 806 AN: 152334 Hom.: 7 Cov.: 32 AF XY: 0.00487 AC XY: 363 AN XY: 74480

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00955

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00810 Hom.: 8

Bravo AF: 0.00467

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CYFIP1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.50
Cadd	Benign	0.85
Dann	Benign	0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs146791821; hg19: chr15-22998470; COSMIC: COSV57406344;