rs115512378

Variant names:

• chr15-22870187-C-T
• rs115512378
• NM_014608.6:c.3603G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3 BP6_Very_Strong BP7 BS1 BS2

The NM_014608.6(CYFIP1):​c.3603G>A​(p.Leu1201Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,609,202 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: CYFIP1 NM_014608.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• 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 -16 ACMG points.

• PP3: BayesDel_noAF computational evidence supports a deleterious effect, 0.26
• BP6: Variant 15-22870187-C-T is Benign according to our data. Variant chr15-22870187-C-T is described in ClinVar as [Benign]. Clinvar id is 781719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00905 (1379/152328) while in subpopulation AFR AF = 0.0303 (1260/41566). AF 95% confidence interval is 0.0289. There are 21 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYFIP1	NM_014608.6	c.3603G>A	p.Leu1201Leu	synonymous_variant	Exon 31 of 31	ENST00000617928.5	NP_055423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYFIP1	ENST00000617928.5	c.3603G>A	p.Leu1201Leu	synonymous_variant	Exon 31 of 31	1	NM_014608.6	ENSP00000481038.1

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1377 AN: 152210 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00267 AC: 656 AN: 246036 AF XY: 0.00213

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00117 AC: 1711 AN: 1456874 Hom.: 32 Cov.: 31 AF XY: 0.00104 AC XY: 756 AN XY: 724666

African (AFR) AF: 0.0310 AC: 1027 AN: 33124

American (AMR) AF: 0.00224 AC: 98 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.00687 AC: 179 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39300

South Asian (SAS) AF: 0.0000470 AC: 4 AN: 85160

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5754

European-Non Finnish (NFE) AF: 0.000186 AC: 207 AN: 1110156

Other (OTH) AF: 0.00299 AC: 180 AN: 60244

GnomAD4 genome AF: 0.00905 AC: 1379 AN: 152328 Hom.: 21 Cov.: 33 AF XY: 0.00862 AC XY: 642 AN XY: 74488

African (AFR) AF: 0.0303 AC: 1260 AN: 41566

American (AMR) AF: 0.00235 AC: 36 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68034

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00504 Hom.: 7

Bravo AF: 0.0102

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	8.5
DANN	Benign	0.61
PhyloP100		1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115512378; hg19: chr15-23002881;