19-51644031-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001098612.3(SIGLEC14):c.760C>T(p.Arg254Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,506,058 control chromosomes in the GnomAD database, including 4 homozygotes. 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: 𝑓 0.000036 ( 1 hom., cov: 25)

Exomes 𝑓: 0.000031 ( 3 hom. )

Consequence

SIGLEC14
NM_001098612.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.185

Variant links:

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]

SIGLEC14 links:

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]

SIGLEC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13503504).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC14	NM_001098612.3 link	c.760C>T	p.Arg254Trp	missense_variant	Exon 5 of 7	ENST00000360844.7	NP_001092082.1	Q08ET2
SIGLEC14	XM_047437991.1 link	c.723C>T	p.Cys241Cys	synonymous_variant	Exon 5 of 5		XP_047293947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIGLEC14	ENST00000360844.7 link	c.760C>T	p.Arg254Trp	missense_variant	Exon 5 of 7	1	NM_001098612.3	ENSP00000354090.5	Q08ET2
SIGLEC14	ENST00000533866.1 link	n.107C>T		non_coding_transcript_exon_variant	Exon 2 of 5	4
SIGLEC5	ENST00000534261.4 link	n.69+1446C>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0000360

AC:

AN:

139038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000208

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:

0.0000308

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000780

AC:

AN:

205094

Hom.:

AF XY:

0.0000633

AC XY:

AN XY:

110662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000456

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:

0.0000206

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1367020

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

676066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000392

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:

0.0000235

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000360

AC:

AN:

139038

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

67300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000208

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000308

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000622

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.760C>T (p.R254W) alteration is located in exon 5 (coding exon 5) of the SIGLEC14 gene. This alteration results from a C to T substitution at nucleotide position 760, causing the arginine (R) at amino acid position 254 to be replaced by a tryptophan (W). 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

-0.44

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.16

M_CAP

Benign

0.0052

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.11

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.21

MutPred

0.67

Loss of MoRF binding (P = 0.0567);

MVP

0.17

MPC

0.52

ClinPred

0.28

GERP RS

1.5

Varity_R

0.11

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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