19-51643805-T-A

Variant names:

• chr19-51643805-T-A
• rs766785830
• NM_001098612.3:c.986A>T

Variant summary

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

The NM_001098612.3(SIGLEC14):​c.986A>T​(p.His329Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,385,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIGLEC14 NM_001098612.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0840

Genes affected

SIGLEC14 (HGNC:32926): (sialic acid binding Ig like lectin 14) Predicted to enable sialic acid binding activity. Predicted to be involved in cell adhesion. Predicted to be located in ficolin-1-rich granule membrane and tertiary granule membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SIGLEC5 (HGNC:10874): (sialic acid binding Ig like lectin 5) This gene encodes a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family. These cell surface lectins are characterized by structural motifs in the immunoglobulin (Ig)-like domains and sialic acid recognition sites in the first Ig V set domain. The encoded protein is a member of the CD33-related subset of Siglecs and inhibits the activation of several cell types including monocytes, macrophages and neutrophils. Binding of group B Streptococcus (GBS) to the encoded protein plays a role in GBS immune evasion. [provided by RefSeq, Feb 2012]

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=0.17206123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC14	NM_001098612.3	c.986A>T	p.His329Leu	missense_variant	Exon 5 of 7	ENST00000360844.7	NP_001092082.1
SIGLEC14	XM_047437991.1	c.*217A>T		downstream_gene_variant			XP_047293947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC14	ENST00000360844.7	c.986A>T	p.His329Leu	missense_variant	Exon 5 of 7	1	NM_001098612.3	ENSP00000354090.5
SIGLEC14	ENST00000533866.1	n.333A>T		non_coding_transcript_exon_variant	Exon 2 of 5	4
SIGLEC5	ENST00000534261.4	n.69+1672A>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000444 AC: 1 AN: 225454 Hom.: 0 AF XY: 0.00000819 AC XY: 1 AN XY: 122060

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: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385556 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 687166

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: 0.00000187

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000882 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.986A>T (p.H329L) alteration is located in exon 5 (coding exon 5) of the SIGLEC14 gene. This alteration results from a A to T substitution at nucleotide position 986, causing the histidine (H) at amino acid position 329 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.020	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.041
Sift	Benign	0.062	T
Sift4G	Benign	0.15	T
Polyphen		0.69	P
Vest4		0.26
MutPred		0.43		Loss of catalytic residue at H329 (P = 0.0437);
MVP		0.20
MPC		0.16
ClinPred		0.50	T
GERP RS		3.1
Varity_R		0.17
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766785830; hg19: chr19-52147058;