NM_053003.4:c.1637C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_053003.4(SIGLEC12):c.1637C>A(p.Pro546Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0997 in 1,597,632 control chromosomes in the GnomAD database, including 8,710 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. P546L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 937 hom., cov: 31)

Exomes 𝑓: 0.099 ( 7773 hom. )

Consequence

SIGLEC12
NM_053003.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.273

Publications

12 publications found

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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0019309521).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC12	NM_053003.4 link	c.1637C>A	p.Pro546Gln	missense_variant	Exon 8 of 8	ENST00000291707.8	NP_443729.1	Q96PQ1-1
SIGLEC12	NM_033329.2 link	c.1283C>A	p.Pro428Gln	missense_variant	Exon 7 of 7		NP_201586.1	Q96PQ1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIGLEC12	ENST00000291707.8 link	c.1637C>A	p.Pro546Gln	missense_variant	Exon 8 of 8	1	NM_053003.4	ENSP00000291707.3	Q96PQ1-1
SIGLEC12	ENST00000596742.1 link	n.*852C>A		non_coding_transcript_exon_variant	Exon 8 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000596742.1 link	n.*852C>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000598614.1 link	c.1283C>A	p.Pro428Gln	missense_variant	Exon 7 of 7	5		ENSP00000472873.1	Q96PQ1-2

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16169

AN:

151862

Hom.:

936

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.0797

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0309

Gnomad FIN

AF:

0.0999

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.0888

AC:

20974

AN:

236174

AF XY:

0.0880

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.0538

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.000221

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0990

AC:

143088

AN:

1445652

Hom.:

7773

Cov.:

AF XY:

0.0972

AC XY:

69807

AN XY:

717816

show subpopulations

African (AFR)

AF:

0.139

AC:

4577

AN:

33026

American (AMR)

AF:

0.0562

AC:

2427

AN:

43216

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

3058

AN:

24864

East Asian (EAS)

AF:

0.000228

AC:

AN:

39520

South Asian (SAS)

AF:

0.0378

AC:

3176

AN:

84076

European-Finnish (FIN)

AF:

0.109

AC:

5609

AN:

51472

Middle Eastern (MID)

AF:

0.104

AC:

586

AN:

5642

European-Non Finnish (NFE)

AF:

0.107

AC:

117789

AN:

1104094

Other (OTH)

AF:

0.0980

AC:

5857

AN:

59742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

7278

14556

21835

29113

36391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.106

AC:

16182

AN:

151980

Hom.:

937

Cov.:

AF XY:

0.103

AC XY:

7686

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.137

AC:

5679

AN:

41416

American (AMR)

AF:

0.0793

AC:

1212

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

425

AN:

3470

East Asian (EAS)

AF:

0.000388

AC:

AN:

5158

South Asian (SAS)

AF:

0.0314

AC:

151

AN:

4814

European-Finnish (FIN)

AF:

0.0999

AC:

1058

AN:

10588

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.106

AC:

7215

AN:

67948

Other (OTH)

AF:

0.108

AC:

227

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

701

1402

2104

2805

3506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0964

Hom.:

576

Bravo

AF:

0.107

TwinsUK

AF:

0.101

AC:

376

ALSPAC

AF:

0.102

AC:

392

ESP6500AA

AF:

0.140

AC:

615

ESP6500EA

AF:

0.110

AC:

948

ExAC

AF:

0.0898

AC:

10898

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.74

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0042

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

PhyloP100

-0.27

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.68

N;.

REVEL

Benign

0.033

Sift

Benign

0.17

T;.

Sift4G

Benign

0.40

T;T

Polyphen

0.90

P;P

Vest4

0.048

MPC

0.17

ClinPred

0.0043

GERP RS

-1.2

Varity_R

0.023

gMVP

0.059

Mutation Taster

=99/1

polymorphism (auto)

(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

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NM_053003.4:c.1637C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over