19-51125242-C-G

Variant names:

• chr19-51125242-C-G
• rs746104514
• NM_014441.3:c.268C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014441.3(SIGLEC9):​c.268C>G​(p.Arg90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SIGLEC9 NM_014441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.543

Genes affected

SIGLEC9 (HGNC:10878): (sialic acid binding Ig like lectin 9) Predicted to enable monosaccharide binding activity and sialic acid binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within negative regulation of inflammatory response and negative regulation of phagocytosis, engulfment. Predicted to be located in external side of plasma membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC9	NM_014441.3	c.268C>G	p.Arg90Gly	missense_variant	Exon 1 of 7	ENST00000250360.8	NP_055256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC9	ENST00000250360.8	c.268C>G	p.Arg90Gly	missense_variant	Exon 1 of 7	1	NM_014441.3	ENSP00000250360.2
SIGLEC9	ENST00000440804.7	c.268C>G	p.Arg90Gly	missense_variant	Exon 1 of 7	2		ENSP00000413861.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251418 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>G (p.R90G) alteration is located in exon 1 (coding exon 1) of the SIGLEC9 gene. This alteration results from a C to G substitution at nucleotide position 268, causing the arginine (R) at amino acid position 90 to be replaced by a glycine (G). 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	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.52
MutPred		0.87		Loss of catalytic residue at R90 (P = 0.015);Loss of catalytic residue at R90 (P = 0.015);
MVP		0.71
MPC		0.82
ClinPred		0.82	D
GERP RS		0.43
Varity_R		0.76
gMVP		0.66

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: rs746104514; hg19: chr19-51628499;