4-48505564-T-C

Position:

• chr4-48505564-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015030.2(FRYL):​c.8446A>G​(p.Ile2816Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FRYL NM_015030.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07244399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRYL	NM_015030.2	c.8446A>G	p.Ile2816Val	missense_variant	60/64	ENST00000358350.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRYL	ENST00000358350.9	c.8446A>G	p.Ile2816Val	missense_variant	60/64	5	NM_015030.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455466 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.8446A>G (p.I2816V) alteration is located in exon 60 (coding exon 57) of the FRYL gene. This alteration results from a A to G substitution at nucleotide position 8446, causing the isoleucine (I) at amino acid position 2816 to be replaced by a valine (V). 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	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.74
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.042
Sift	Benign	0.75	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.41		Loss of stability (P = 0.0904);Loss of stability (P = 0.0904);
MVP		0.093
MPC		0.20
ClinPred		0.040	T
GERP RS		3.5
Varity_R		0.027
gMVP		0.073

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs1159981790; hg19: chr4-48507581;