chr15-22874544-C-T

Variant names:

• chr15-22874544-C-T
• rs534254052
• NM_014608.6:c.3210+6G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014608.6(CYFIP1):​c.3210+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 1,591,666 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (12 hom.)
• Consequence: CYFIP1 NM_014608.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001082
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.09
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-22874544-C-T is Benign according to our data. Variant chr15-22874544-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3047926.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 gene

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.3210+6G>A		splice_region intron	N/A	NP_055423.1	Q7L576-1
	CYFIP1	NM_001324119.2		c.3312+6G>A		splice_region intron	N/A	NP_001311048.1
	CYFIP1	NM_001287810.4		c.3210+6G>A		splice_region intron	N/A	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.3210+6G>A		splice_region intron	N/A	ENSP00000481038.1	Q7L576-1
	CYFIP1	ENST00000610365.4	TSL:1	c.3210+6G>A		splice_region intron	N/A	ENSP00000478779.1	Q7L576-1
	CYFIP1	ENST00000617556.4	TSL:1	c.1917+6G>A		splice_region intron	N/A	ENSP00000480525.1	Q7L576-2

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152228 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: 0.00135

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00104 AC: 234 AN: 224120 AF XY: 0.00139

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.0000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000303

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000193

Gnomad OTH exome AF: 0.000744

GnomAD4 exome AF: 0.000556 AC: 800 AN: 1439320 Hom.: 12 Cov.: 29 AF XY: 0.000764 AC XY: 547 AN XY: 715930

African (AFR) AF: 0.0000936 AC: 3 AN: 32040

American (AMR) AF: 0.0000253 AC: 1 AN: 39478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00295 AC: 114 AN: 38688

South Asian (SAS) AF: 0.00776 AC: 639 AN: 82360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5668

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1103196

Other (OTH) AF: 0.000589 AC: 35 AN: 59430

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.0000680

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CYFIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.4
DANN	Benign	0.64
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.17		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: rs534254052; hg19: chr15-22998524; COSMIC: COSV57414972;