dbSNP rs201786850: SIGLEC14:p.Trp286Cys (chr19-51643933-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001098612.3(SIGLEC14):c.858G>T(p.Trp286Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,534,104 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 4 hom., cov: 25)

Exomes 𝑓: 0.00025 ( 55 hom. )

Consequence

SIGLEC14
NM_001098612.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098612.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC14	NM_001098612.3	MANE Select	c.858G>T	p.Trp286Cys	missense	Exon 5 of 7	NP_001092082.1	Q08ET2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIGLEC14	ENST00000360844.7	TSL:1 MANE Select	c.858G>T	p.Trp286Cys	missense	Exon 5 of 7	ENSP00000354090.5	Q08ET2
SIGLEC14	ENST00000533866.1	TSL:4	n.205G>T		non_coding_transcript_exon	Exon 2 of 5
SIGLEC5	ENST00000534261.4	TSL:5	n.69+1544G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000129

AC:

AN:

139288

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000262

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000117

AC:

AN:

231146

AF XY:

0.000135

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000252

AC:

352

AN:

1394816

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

172

AN XY:

693174

show subpopulations

African (AFR)

AF:

0.0000968

AC:

AN:

30992

American (AMR)

AF:

0.00

AC:

AN:

43538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25292

East Asian (EAS)

AF:

0.00

AC:

AN:

26026

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.000315

AC:

339

AN:

1076858

Other (OTH)

AF:

0.000157

AC:

AN:

57174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000129

AC:

AN:

139288

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

67438

show subpopulations

African (AFR)

AF:

0.0000272

AC:

AN:

36762

American (AMR)

AF:

0.00

AC:

AN:

14502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3318

East Asian (EAS)

AF:

0.00

AC:

AN:

2936

South Asian (SAS)

AF:

0.00

AC:

AN:

4106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.000262

AC:

AN:

64924

Other (OTH)

AF:

0.00

AC:

AN:

1942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000183

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.0000972

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.098

Eigen

Benign

0.11

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0065

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.75

MutationAssessor

Pathogenic

4.2

PhyloP100

1.0

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-11

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.64

MutPred

0.86

Loss of catalytic residue at L284 (P = 0.0028)

MVP

0.47

MPC

0.73

ClinPred

0.98

GERP RS

0.83

Varity_R

0.67

gMVP

0.86

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over