4-48500184-T-G

Variant names:

• chr4-48500184-T-G
• rs62619178
• NM_015030.2:c.8629A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015030.2(FRYL):​c.8629A>C​(p.Ser2877Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2877G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FRYL NM_015030.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07966447).

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.8629A>C	p.Ser2877Arg	missense	Exon 63 of 64	NP_055845.1	O94915-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRYL	ENST00000358350.9	TSL:5 MANE Select	c.8629A>C	p.Ser2877Arg	missense	Exon 63 of 64	ENSP00000351113.4	O94915-1
	FRYL	ENST00000507873.8	TSL:1	c.8611A>C	p.Ser2871Arg	missense	Exon 59 of 60	ENSP00000422408.4	A0A2C9F2R7
	FRYL	ENST00000512810.1	TSL:1	n.1084A>C		non_coding_transcript_exon	Exon 8 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443426 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 717944

African (AFR) AF: 0.00 AC: 0 AN: 32112

American (AMR) AF: 0.00 AC: 0 AN: 37998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25602

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.00 AC: 0 AN: 81670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108198

Other (OTH) AF: 0.00 AC: 0 AN: 59530

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.017
Sift	Benign	0.58	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.31		Gain of helix (P = 0.027)
MVP		0.17
MPC		0.28
ClinPred		0.32	T
GERP RS		3.4
Varity_R		0.031
gMVP		0.33
Mutation Taster		=62/38	polymorphism

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: rs62619178; hg19: chr4-48502201;