rs7170637

Variant names:

• chr15-22903836-C-T
• rs7170637
• NM_014608.6:c.2458G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014608.6(CYFIP1):​c.2458G>A​(p.Gly820Ser) variant causes a missense change. The variant allele was found at a frequency of 0.179 in 1,613,908 control chromosomes in the GnomAD database, including 35,131 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G820D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.29 (9387 hom., cov: 33)
  • Exomes 𝑓: 0.17 (25744 hom.)
• Consequence: CYFIP1 NM_014608.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048214793).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYFIP1	NM_014608.6	c.2458G>A	p.Gly820Ser	missense_variant	Exon 22 of 31	ENST00000617928.5	NP_055423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYFIP1	ENST00000617928.5	c.2458G>A	p.Gly820Ser	missense_variant	Exon 22 of 31	1	NM_014608.6	ENSP00000481038.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43334 AN: 152008 Hom.: 9365 Cov.: 33

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.177 AC: 44486 AN: 251312 AF XY: 0.171

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.000761

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.168 AC: 246207 AN: 1461782 Hom.: 25744 Cov.: 32 AF XY: 0.167 AC XY: 121302 AN XY: 727194

Gnomad4 AFR exome AF: 0.625 AC: 20920 AN: 33478

Gnomad4 AMR exome AF: 0.110 AC: 4909 AN: 44722

Gnomad4 ASJ exome AF: 0.151 AC: 3944 AN: 26136

Gnomad4 EAS exome AF: 0.000453 AC: 18 AN: 39698

Gnomad4 SAS exome AF: 0.131 AC: 11300 AN: 86256

Gnomad4 FIN exome AF: 0.233 AC: 12453 AN: 53384

Gnomad4 NFE exome AF: 0.162 AC: 180257 AN: 1111948

Gnomad4 Remaining exome AF: 0.183 AC: 11028 AN: 60392

GnomAD4 genome AF: 0.285 AC: 43400 AN: 152126 Hom.: 9387 Cov.: 33 AF XY: 0.279 AC XY: 20745 AN XY: 74374

Gnomad4 AFR AF: 0.609 AC: 0.608962 AN: 0.608962

Gnomad4 AMR AF: 0.171 AC: 0.17144 AN: 0.17144

Gnomad4 ASJ AF: 0.154 AC: 0.153802 AN: 0.153802

Gnomad4 EAS AF: 0.00213 AC: 0.00212684 AN: 0.00212684

Gnomad4 SAS AF: 0.123 AC: 0.123495 AN: 0.123495

Gnomad4 FIN AF: 0.239 AC: 0.23863 AN: 0.23863

Gnomad4 NFE AF: 0.163 AC: 0.162529 AN: 0.162529

Gnomad4 OTH AF: 0.261 AC: 0.261342 AN: 0.261342

Alfa AF: 0.204 Hom.: 11454

Bravo AF: 0.298

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	19
DANN	Benign	0.73
DEOGEN2	Benign	0.054	T;.;T
LIST_S2	Benign	0.66	.;T;T
MetaRNN	Benign	0.0048	T;T;T
Sift4G	Benign	0.78	T;T;T
Vest4		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs7170637; hg19: chr15-22969232;