chr19-51491826-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_053003.4(SIGLEC12):c.1603C>A(p.Pro535Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SIGLEC12
NM_053003.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.121

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0559631).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC12	NM_053003.4 link	c.1603C>A	p.Pro535Thr	missense_variant	Exon 8 of 8	ENST00000291707.8	NP_443729.1	Q96PQ1-1
SIGLEC12	NM_033329.2 link	c.1249C>A	p.Pro417Thr	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.1603C>A	p.Pro535Thr	missense_variant	Exon 8 of 8	1	NM_053003.4	ENSP00000291707.3	Q96PQ1-1
SIGLEC12	ENST00000596742.1 link	n.*818C>A		non_coding_transcript_exon_variant	Exon 8 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000596742.1 link	n.*818C>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000598614.1 link	c.1249C>A	p.Pro417Thr	missense_variant	Exon 7 of 7	5		ENSP00000472873.1	Q96PQ1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1403390

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31938

American (AMR)

AF:

0.00

AC:

AN:

38730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22322

East Asian (EAS)

AF:

0.00

AC:

AN:

39260

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085678

Other (OTH)

AF:

0.00

AC:

AN:

58092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1603C>A (p.P535T) alteration is located in exon 8 (coding exon 8) of the SIGLEC12 gene. This alteration results from a C to A substitution at nucleotide position 1603, causing the proline (P) at amino acid position 535 to be replaced by a threonine (T). 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

0.070

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.42

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.0065

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.064

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.88

L;.

PhyloP100

0.12

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.035

Sift

Benign

0.34

T;.

Sift4G

Benign

0.20

T;T

Polyphen

0.0010

B;B

Vest4

0.096

MutPred

0.18

Gain of phosphorylation at P535 (P = 0.0444);.;

MVP

0.081

MPC

0.048

ClinPred

0.046

GERP RS

-4.0

Varity_R

0.038

gMVP

0.075

Mutation Taster

=98/2

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

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chr19-51491826-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over