chr19-51491828-C-G

Variant names:

• chr19-51491828-C-G
• rs1364652112
• NM_053003.4:c.1601G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053003.4(SIGLEC12):​c.1601G>C​(p.Gly534Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000515 in 1,553,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G534V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SIGLEC12 NM_053003.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004432
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333
• Publications: 1 publications found

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]

ACMG classification

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=0.07324836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC12	NM_053003.4	c.1601G>C	p.Gly534Ala	missense_variant, splice_region_variant	Exon 8 of 8	ENST00000291707.8	NP_443729.1
SIGLEC12	NM_033329.2	c.1247G>C	p.Gly416Ala	missense_variant, splice_region_variant	Exon 7 of 7		NP_201586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC12	ENST00000291707.8	c.1601G>C	p.Gly534Ala	missense_variant, splice_region_variant	Exon 8 of 8	1	NM_053003.4	ENSP00000291707.3
SIGLEC12	ENST00000596742.1	n.*816G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 8	1		ENSP00000469791.1
SIGLEC12	ENST00000596742.1	n.*816G>C		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000469791.1
SIGLEC12	ENST00000598614.1	c.1247G>C	p.Gly416Ala	missense_variant, splice_region_variant	Exon 7 of 7	5		ENSP00000472873.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151900 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000500 AC: 7 AN: 1401368 Hom.: 0 Cov.: 31 AF XY: 0.00000434 AC XY: 3 AN XY: 691460

African (AFR) AF: 0.00 AC: 0 AN: 31844

American (AMR) AF: 0.00 AC: 0 AN: 38394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22220

East Asian (EAS) AF: 0.00 AC: 0 AN: 39214

South Asian (SAS) AF: 0.00 AC: 0 AN: 76946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5334

European-Non Finnish (NFE) AF: 0.00000645 AC: 7 AN: 1084900

Other (OTH) AF: 0.00 AC: 0 AN: 58030

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151900 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74150

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.1
DANN	Benign	0.77
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		-0.33
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.058
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.044	D;T
Polyphen		0.14	B;P
Vest4		0.084
MutPred		0.14		Loss of catalytic residue at G534 (P = 0.0946);.;
MVP		0.19
MPC		0.056
ClinPred		0.12	T
GERP RS		-0.69
Varity_R		0.12
gMVP		0.064
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs1364652112; hg19: chr19-51995082;