Genetic Variant NM_014608.6:c.3603G>A (chr15-22870187-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3BP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.77

Publications

1 publications found

Variant links:

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]

CYFIP1 links:

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ACMG classification

Classification was made for transcript

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 link	c.3603G>A	p.Leu1201Leu	synonymous_variant	Exon 31 of 31	ENST00000617928.5	NP_055423.1	Q7L576-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYFIP1	ENST00000617928.5 link	c.3603G>A	p.Leu1201Leu	synonymous_variant	Exon 31 of 31	1	NM_014608.6	ENSP00000481038.1		Q7L576-1

Frequencies

GnomAD3 genomes

AF:

0.00905

AC:

1377

AN:

152210

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00104

AC XY:

756

AN XY:

724666

show subpopulations

African (AFR)

AF:

0.0310

AC:

1027

AN:

33124

American (AMR)

AF:

0.00224

AC:

AN:

43694

Ashkenazi Jewish (ASJ)

AF:

0.00687

AC:

179

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39300

South Asian (SAS)

AF:

0.0000470

AC:

AN:

85160

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000186

AC:

207

AN:

1110156

Other (OTH)

AF:

0.00299

AC:

180

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00905

AC:

1379

AN:

152328

Hom.:

Cov.:

AF XY:

0.00862

AC XY:

642

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0303

AC:

1260

AN:

41566

American (AMR)

AF:

0.00235

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68034

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

135

203

270

338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00504

Hom.:

Bravo

AF:

0.0102

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

(source)

DANN

Benign

0.61

PhyloP100

1.8

Splicing

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

Publications

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NM_014608.6:c.3603G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over