rs770909069

Variant names:

• chr15-22873540-T-A
• rs770909069
• NM_014608.6:c.3400A>T

Your query was ambiguous. Multiple possible variants found:

• chr15-22873540-T-A
• chr15-22873540-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014608.6(CYFIP1):​c.3400A>T​(p.Met1134Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYFIP1 NM_014608.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32173836).

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.3400A>T	p.Met1134Leu	missense	Exon 29 of 31	NP_055423.1	Q7L576-1
	CYFIP1	NM_001324119.2		c.3502A>T	p.Met1168Leu	missense	Exon 29 of 31	NP_001311048.1
	CYFIP1	NM_001287810.4		c.3400A>T	p.Met1134Leu	missense	Exon 30 of 32	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.3400A>T	p.Met1134Leu	missense	Exon 29 of 31	ENSP00000481038.1	Q7L576-1
	CYFIP1	ENST00000610365.4	TSL:1	c.3400A>T	p.Met1134Leu	missense	Exon 30 of 32	ENSP00000478779.1	Q7L576-1
	CYFIP1	ENST00000617556.4	TSL:1	c.2107A>T	p.Met703Leu	missense	Exon 14 of 16	ENSP00000480525.1	Q7L576-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251292 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.070	T
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.32	T
PhyloP100		8.0
PROVEAN	Benign	-0.60	N
Sift	Benign	0.96	T
Sift4G	Benign	0.97	T
Vest4		0.73
gMVP		0.96

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

Other links and lift over

dbSNP: rs770909069; hg19: chr15-22999528;