2-16565698-C-T

Variant names:

• chr2-16565698-C-T
• rs1666903839
• NM_030797.4:c.140G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030797.4(CYRIA):​c.140G>A​(p.Ser47Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: 6.9e-7 (0 hom.)
• Consequence: CYRIA NM_030797.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1586434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYRIA	NM_030797.4	c.140G>A	p.Ser47Asn	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.140G>A	p.Ser47Asn	missense_variant	Exon 4 of 12	1	NM_030797.4	ENSP00000370724.3
CYRIA	ENST00000406434.5	c.140G>A	p.Ser47Asn	missense_variant	Exon 5 of 13	5		ENSP00000384771.1
CYRIA	ENST00000445605.5	c.140G>A	p.Ser47Asn	missense_variant	Exon 4 of 5	4		ENSP00000392154.1
CYRIA	ENST00000451689.1	c.140G>A	p.Ser47Asn	missense_variant	Exon 5 of 6	4		ENSP00000388979.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442412 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715716

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140G>A (p.S47N) alteration is located in exon 1 (coding exon 1) of the FAM49A gene. This alteration results from a G to A substitution at nucleotide position 140, causing the serine (S) at amino acid position 47 to be replaced by an asparagine (N). 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	0.061
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;.;.
Eigen	Benign	0.0077
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N;N;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.75	N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.49	T;T;T;T
Sift4G	Benign	0.49	T;T;T;.
Polyphen		0.0060	B;B;.;.
Vest4		0.21
MutPred		0.28		Loss of phosphorylation at S47 (P = 0.0855);Loss of phosphorylation at S47 (P = 0.0855);Loss of phosphorylation at S47 (P = 0.0855);Loss of phosphorylation at S47 (P = 0.0855);
MVP		0.093
MPC		0.92
ClinPred		0.60	D
GERP RS		5.3
Varity_R		0.24
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1666903839; hg19: chr2-16746966;