Genetic Variant FRYL:p.Met2767Ile (chr4-48510152-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015030.2(FRYL):c.8301G>T(p.Met2767Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,610,536 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 1 hom. )

Consequence

FRYL
NM_015030.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

Publications

4 publications found

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]

FRYL Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Pan-Chung-Bellen syndrome
Inheritance: AD Classification: MODERATE Submitted by: G2P

FRYL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039807767).

BS2

High AC in GnomAd4 at 80 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015030.2. 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
	FRYL	NM_015030.2	MANE Select	c.8301G>T	p.Met2767Ile	missense	Exon 59 of 64	NP_055845.1	O94915-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRYL	ENST00000358350.9	TSL:5 MANE Select	c.8301G>T	p.Met2767Ile	missense	Exon 59 of 64	ENSP00000351113.4	O94915-1
FRYL	ENST00000507873.8	TSL:1	c.8301G>T	p.Met2767Ile	missense	Exon 56 of 60	ENSP00000422408.4	A0A2C9F2R7
FRYL	ENST00000512810.1	TSL:1	n.774G>T		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000418

AC:

104

AN:

249078

AF XY:

0.000422

show subpopulations

Gnomad AFR exome

AF:

0.000194

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:

0.000868

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000680

AC:

992

AN:

1458334

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

469

AN XY:

725696

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

33386

American (AMR)

AF:

0.0000224

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000868

AC:

963

AN:

1108906

Other (OTH)

AF:

0.000299

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000526

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000756

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.00133

AC:

ExAC

AF:

0.000389

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.022

Eigen

Benign

-0.15

Eigen_PC

Benign

0.0094

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

M_CAP

Benign

0.0050

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

1.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.85

REVEL

Benign

0.062

Sift

Benign

0.39

Sift4G

Benign

0.35

Polyphen

0.0080

Vest4

0.33

MutPred

0.35

Gain of catalytic residue at L2772 (P = 0.0651)

MVP

0.10

MPC

0.27

ClinPred

0.030

GERP RS

5.9

Varity_R

0.13

gMVP

0.23

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over