Genetic Variant CYRIA:p.Asn180His (chr2-16561253-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_030797.4(CYRIA):c.538A>C(p.Asn180His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,613,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

CYRIA
NM_030797.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYRIA	NM_030797.4 link	c.538A>C	p.Asn180His	missense_variant	Exon 8 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.538A>C	p.Asn180His	missense_variant	Exon 8 of 12	1	NM_030797.4	ENSP00000370724.3	Q9H0Q0
CYRIA	ENST00000406434.5 link	c.538A>C	p.Asn180His	missense_variant	Exon 9 of 13	5		ENSP00000384771.1	Q9H0Q0
CYRIA	ENST00000469507.1 link	n.52A>C		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

250316

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135250

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:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000315

AC:

460

AN:

1460914

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

216

AN XY:

726856

show subpopulations

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:

0.000407

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000105

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538A>C (p.N180H) alteration is located in exon 1 (coding exon 1) of the FAM49A gene. This alteration results from a A to C substitution at nucleotide position 538, causing the asparagine (N) at amino acid position 180 to be replaced by a histidine (H). 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

Uncertain

0.42

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.96

D;D

Vest4

0.81

MVP

0.54

MPC

2.1

ClinPred

0.43

GERP RS

5.7

Varity_R

0.47

gMVP

0.78

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

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