4-48500154-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015030.2(FRYL):​c.8659G>A​(p.Glu2887Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,606,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

FRYL
NM_015030.2 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67
Variant links:
Genes affected
FRYL (HGNC:29127): (FRY like transcription coactivator) Predicted to be involved in cell morphogenesis and neuron projection development. Predicted to be active in cell cortex and site of polarized growth. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06628117).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FRYLNM_015030.2 linkc.8659G>A p.Glu2887Lys missense_variant Exon 63 of 64 ENST00000358350.9 NP_055845.1 O94915-1B3KXG5Q6ZR29

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRYLENST00000358350.9 linkc.8659G>A p.Glu2887Lys missense_variant Exon 63 of 64 5 NM_015030.2 ENSP00000351113.4 O94915-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000206
AC:
5
AN:
242310
Hom.:
0
AF XY:
0.00000760
AC XY:
1
AN XY:
131542
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000623
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000573
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000199
AC:
29
AN:
1454264
Hom.:
0
Cov.:
30
AF XY:
0.0000152
AC XY:
11
AN XY:
723302
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000949
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000238
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.8659G>A (p.E2887K) alteration is located in exon 63 (coding exon 60) of the FRYL gene. This alteration results from a G to A substitution at nucleotide position 8659, causing the glutamic acid (E) at amino acid position 2887 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.078
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.049
T;T
Eigen
Benign
-0.070
Eigen_PC
Benign
0.064
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.92
.;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.066
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.060
Sift
Benign
0.13
T;T
Sift4G
Benign
0.13
T;T
Polyphen
0.024
B;B
Vest4
0.14
MVP
0.10
MPC
0.29
ClinPred
0.36
T
GERP RS
5.1
Varity_R
0.12
gMVP
0.26

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs540707705; hg19: chr4-48502171; COSMIC: COSV99976741; API