13-32124809-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_023037.3(FRY):c.650A>G(p.Asn217Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,276 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: 0.0000089 (0 hom.)
• Consequence: FRY NM_023037.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

FRY (HGNC:20367): (FRY microtubule binding protein) Predicted to enable enzyme inhibitor activity. Predicted to be involved in cell morphogenesis and neuron projection development. Predicted to be located in microtubule organizing center and spindle pole. Predicted to be active in cell cortex and site of polarized growth. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FRY
• BP4: Computational evidence support a benign effect (MetaRNN=0.40337467).
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRY	NM_023037.3	c.650A>G	p.Asn217Ser	missense_variant	7/61	ENST00000542859.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRY	ENST00000542859.6	c.650A>G	p.Asn217Ser	missense_variant	7/61	5	NM_023037.3	A1
FRY	ENST00000647500.1	c.785A>G	p.Asn262Ser	missense_variant	7/61
FRY	ENST00000642040.1	c.650A>G	p.Asn217Ser	missense_variant	7/62			P4
FRY	ENST00000645780.1	c.500A>G	p.Asn167Ser	missense_variant	8/62

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249468 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460276 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

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

Dec 09, 2023

The c.650A>G (p.N217S) alteration is located in exon 7 (coding exon 7) of the FRY gene. This alteration results from a A to G substitution at nucleotide position 650, causing the asparagine (N) at amino acid position 217 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	0.0030	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
Polyphen		0.72	.;.;.;.;P
Vest4		0.54, 0.87
MutPred		0.31		.;.;Gain of glycosylation at N217 (P = 0.0464);Gain of glycosylation at N217 (P = 0.0464);Gain of glycosylation at N217 (P = 0.0464);
MVP		0.35
MPC		1.1
ClinPred		0.50	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754793180; hg19: chr13-32698946;