Genetic Variant SIGLEC12:p.Arg503Thr (chr19-51496971-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_053003.4(SIGLEC12):c.1508G>C(p.Arg503Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R503K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SIGLEC12
NM_053003.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.816

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10804719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC12	NM_053003.4 link	c.1508G>C	p.Arg503Thr	missense_variant	Exon 7 of 8	ENST00000291707.8	NP_443729.1	Q96PQ1-1
SIGLEC12	NM_033329.2 link	c.1154G>C	p.Arg385Thr	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.1508G>C	p.Arg503Thr	missense_variant	Exon 7 of 8	1	NM_053003.4	ENSP00000291707.3	Q96PQ1-1
SIGLEC12	ENST00000596742.1 link	n.*723G>C		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000596742.1 link	n.*723G>C		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000469791.1	M0QYF3
SIGLEC12	ENST00000598614.1 link	c.1154G>C	p.Arg385Thr	missense_variant	Exon 6 of 7	5		ENSP00000472873.1	Q96PQ1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726774

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4988

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.052

T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.0079

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.0043

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

-0.82

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.8

D;.

REVEL

Benign

0.11

Sift

Uncertain

0.019

D;.

Sift4G

Uncertain

0.052

T;T

Polyphen

0.038

B;P

Vest4

0.16

MutPred

0.56

Loss of MoRF binding (P = 0.0082);.;

MVP

0.18

MPC

0.19

ClinPred

0.20

GERP RS

0.62

Varity_R

0.073

gMVP

0.099

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over