2-16565694-G-C

Variant names:

• chr2-16565694-G-C
• rs868421855
• NM_030797.4:c.144C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030797.4(CYRIA):​c.144C>G​(p.Ile48Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,441,792 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CYRIA NM_030797.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
CYRIA	NM_030797.4	c.144C>G	p.Ile48Met	missense_variant	Exon 4 of 12	ENST00000381323.7	NP_110424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYRIA	ENST00000381323.7	c.144C>G	p.Ile48Met	missense_variant	Exon 4 of 12	1	NM_030797.4	ENSP00000370724.3
CYRIA	ENST00000406434.5	c.144C>G	p.Ile48Met	missense_variant	Exon 5 of 13	5		ENSP00000384771.1
CYRIA	ENST00000445605.5	c.144C>G	p.Ile48Met	missense_variant	Exon 4 of 5	4		ENSP00000392154.1
CYRIA	ENST00000451689.1	c.144C>G	p.Ile48Met	missense_variant	Exon 5 of 6	4		ENSP00000388979.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1441792 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 715408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000676

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.144C>G (p.I48M) alteration is located in exon 1 (coding exon 1) of the FAM49A gene. This alteration results from a C to G substitution at nucleotide position 144, causing the isoleucine (I) at amino acid position 48 to be replaced by a methionine (M). 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	0.19
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Benign	0.0060	T
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M;M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.037	D;D;T;T
Sift4G	Benign	0.17	T;T;T;.
Polyphen		0.17	B;B;.;.
Vest4		0.25
MutPred		0.73		Gain of disorder (P = 0.0689);Gain of disorder (P = 0.0689);Gain of disorder (P = 0.0689);Gain of disorder (P = 0.0689);
MVP		0.068
MPC		1.6
ClinPred		0.84	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs868421855; hg19: chr2-16746962;