19-51496933-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_053003.4(SIGLEC12):c.1546G>A(p.Val516Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,613,696 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V516L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 17 hom., cov: 32)

Exomes 𝑓: 0.018 ( 239 hom. )

Consequence

SIGLEC12
NM_053003.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.777

Variant links:

Genes affected

SIGLEC12 (HGNC:15482): (sialic acid binding Ig like lectin 12) Sialic acid-binding immunoglobulin-like lectins (SIGLECs) are a family of cell surface proteins belonging to the immunoglobulin superfamily. They mediate protein-carbohydrate interactions by selectively binding to different sialic acid moieties present on glycolipids and glycoproteins. This gene encodes a member of the SIGLEC3-like subfamily of SIGLECs. Members of this subfamily are characterized by an extracellular V-set immunoglobulin-like domain followed by two C2-set immunoglobulin-like domains, and the cytoplasmic tyrosine-based motifs ITIM and SLAM-like. The encoded protein, upon tyrosine phosphorylation, has been shown to recruit the Src homology 2 domain-containing protein-tyrosine phosphatases SHP1 and SHP2. It has been suggested that the protein is involved in the negative regulation of macrophage signaling by functioning as an inhibitory receptor. This gene is located in a cluster with other SIGLEC3-like genes on 19q13.4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

SIGLEC12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003753513).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0135 (2054/152312) while in subpopulation NFE AF = 0.0214 (1453/68014). AF 95% confidence interval is 0.0204. There are 17 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC12	NM_053003.4 link	c.1546G>A	p.Val516Met	missense_variant	Exon 7 of 8	ENST00000291707.8	NP_443729.1	Q96PQ1-1
SIGLEC12	NM_033329.2 link	c.1192G>A	p.Val398Met	missense_variant	Exon 6 of 7		NP_201586.1	Q96PQ1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIGLEC12	ENST00000291707.8 link	c.1546G>A	p.Val516Met	missense_variant	Exon 7 of 8	1	NM_053003.4	ENSP00000291707.3	Q96PQ1-1
SIGLEC12	ENST00000596742.1 link	n.*761G>A		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000596742.1 link	n.*761G>A		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000598614.1 link	c.1192G>A	p.Val398Met	missense_variant	Exon 6 of 7	5		ENSP00000472873.1	Q96PQ1-2

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2058

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00376

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0214

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.0143

AC:

3589

AN:

251480

AF XY:

0.0153

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00908

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0176

AC:

25698

AN:

1461384

Hom.:

239

Cov.:

AF XY:

0.0178

AC XY:

12946

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

33466

American (AMR)

AF:

0.0102

AC:

458

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

293

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0110

AC:

949

AN:

86222

European-Finnish (FIN)

AF:

0.00721

AC:

385

AN:

53418

Middle Eastern (MID)

AF:

0.0382

AC:

207

AN:

5422

European-Non Finnish (NFE)

AF:

0.0200

AC:

22238

AN:

1111938

Other (OTH)

AF:

0.0177

AC:

1067

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

1435

2869

4304

5738

7173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0135

AC:

2054

AN:

152312

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

921

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00375

AC:

156

AN:

41568

American (AMR)

AF:

0.0117

AC:

179

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00891

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00650

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0214

AC:

1453

AN:

68014

Other (OTH)

AF:

0.0198

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

100

200

299

399

499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0185

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0223

AC:

192

ExAC

AF:

0.0150

AC:

1820

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0225

EpiControl

AF:

0.0251

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.081

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0012

T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00079

LIST_S2

Benign

0.16

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

PhyloP100

-0.78

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.37

N;.

REVEL

Benign

0.10

Sift

Benign

0.036

D;.

Sift4G

Benign

0.21

T;T

Polyphen

0.69

P;B

Vest4

0.18

MPC

0.063

ClinPred

0.0045

GERP RS

-0.17

Varity_R

0.026

gMVP

0.048

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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19-51496933-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over