dbSNP rs755977980: FRY:p.His189Tyr (chr13-32124611-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_023037.3(FRY):c.565C>T(p.His189Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

FRY
NM_023037.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Publications

0 publications found

Variant links:

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]

FRY Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

FRY links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRY	NM_023037.3 link	c.565C>T	p.His189Tyr	missense_variant	Exon 6 of 61	ENST00000542859.6	NP_075463.2	Q5TBA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FRY	ENST00000542859.6 link	c.565C>T	p.His189Tyr	missense_variant	Exon 6 of 61	5	NM_023037.3	ENSP00000445043.2	Q5TBA9
FRY	ENST00000647500.1 link	c.700C>T	p.His234Tyr	missense_variant	Exon 6 of 61			ENSP00000494761.1	A0A2R8Y5V8
FRY	ENST00000642040.1 link	c.565C>T	p.His189Tyr	missense_variant	Exon 6 of 62			ENSP00000493189.1	A0A286YFA9
FRY	ENST00000645780.1 link	c.415C>T	p.His139Tyr	missense_variant	Exon 7 of 62			ENSP00000494080.1	A0A2R8YCY2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248880

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1433674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32876

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25976

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

85652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087022

Other (OTH)

AF:

0.00

AC:

AN:

59358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.565C>T (p.H189Y) alteration is located in exon 6 (coding exon 6) of the FRY gene. This alteration results from a C to T substitution at nucleotide position 565, causing the histidine (H) at amino acid position 189 to be replaced by a tyrosine (Y). 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

0.18

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;.;.;T;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.56

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;.;.;.;M

PhyloP100

7.9

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.2

.;.;.;D;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.021

.;.;.;D;.

Sift4G

Uncertain

0.027

.;.;.;D;D

Polyphen

0.012

.;.;.;.;B

Vest4

0.61, 0.82

MutPred

0.51

.;.;Gain of ubiquitination at K184 (P = 0.0707);Gain of ubiquitination at K184 (P = 0.0707);Gain of ubiquitination at K184 (P = 0.0707);

MVP

0.13

MPC

0.85

ClinPred

0.94

GERP RS

5.5

Varity_R

0.55

gMVP

0.62

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over