Genetic Variant CYRIA:p.Asp51Glu (chr2-16565685-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030797.4(CYRIA):c.153C>A(p.Asp51Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,592,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CYRIA
NM_030797.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

Variant links:

Genes affected

CYRIA (HGNC:25373): (CYFIP related Rac1 interactor A) Predicted to enable small GTPase binding activity. Predicted to be involved in regulation of actin filament polymerization. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CYRIA links:

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ACMG classification

Classification made for transcript

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=0.11262274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYRIA	NM_030797.4 link	c.153C>A	p.Asp51Glu	missense_variant	Exon 4 of 12	ENST00000381323.7	NP_110424.1	Q9H0Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYRIA	ENST00000381323.7 link	c.153C>A	p.Asp51Glu	missense_variant	Exon 4 of 12	1	NM_030797.4	ENSP00000370724.3	Q9H0Q0
CYRIA	ENST00000406434.5 link	c.153C>A	p.Asp51Glu	missense_variant	Exon 5 of 13	5		ENSP00000384771.1	Q9H0Q0
CYRIA	ENST00000445605.5 link	c.153C>A	p.Asp51Glu	missense_variant	Exon 4 of 5	4		ENSP00000392154.1	C9IYV6
CYRIA	ENST00000451689.1 link	c.153C>A	p.Asp51Glu	missense_variant	Exon 5 of 6	4		ENSP00000388979.1	C9JPE5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000561

AC:

AN:

249640

Hom.:

AF XY:

0.0000667

AC XY:

AN XY:

134906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000167

AC:

241

AN:

1440452

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

123

AN XY:

714414

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

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:

0.0000189

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.153C>A (p.D51E) alteration is located in exon 1 (coding exon 1) of the FAM49A gene. This alteration results from a C to A substitution at nucleotide position 153, causing the aspartic acid (D) at amino acid position 51 to be replaced by a glutamic acid (E). 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

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.027

T;T;.;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

.;T;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.28

N;N;N;N

REVEL

Benign

0.040

Sift

Benign

0.81

T;T;T;T

Sift4G

Benign

0.63

T;T;T;.

Polyphen

0.013

B;B;.;.

Vest4

0.062

MutPred

0.44

Gain of ubiquitination at K56 (P = 0.1278);Gain of ubiquitination at K56 (P = 0.1278);Gain of ubiquitination at K56 (P = 0.1278);Gain of ubiquitination at K56 (P = 0.1278);

MVP

0.068

MPC

0.93

ClinPred

0.025

GERP RS

2.3

Varity_R

0.056

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over