NM_053003.4:c.1576G>C

Variant names:

• chr19-51496903-C-G
• NM_053003.4:c.1576G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053003.4(SIGLEC12):​c.1576G>C​(p.Ala526Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A526T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SIGLEC12 NM_053003.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.69

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05814439).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC12	NM_053003.4	c.1576G>C	p.Ala526Pro	missense_variant	Exon 7 of 8	ENST00000291707.8	NP_443729.1
SIGLEC12	NM_033329.2	c.1222G>C	p.Ala408Pro	missense_variant	Exon 6 of 7		NP_201586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC12	ENST00000291707.8	c.1576G>C	p.Ala526Pro	missense_variant	Exon 7 of 8	1	NM_053003.4	ENSP00000291707.3
SIGLEC12	ENST00000596742.1	n.*791G>C		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000469791.1
SIGLEC12	ENST00000596742.1	n.*791G>C		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000469791.1
SIGLEC12	ENST00000598614.1	c.1222G>C	p.Ala408Pro	missense_variant	Exon 6 of 7	5		ENSP00000472873.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.054
DANN	Benign	0.17
DEOGEN2	Benign	0.0040	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00048	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.40	N;.
REVEL	Benign	0.17
Sift	Benign	0.38	T;.
Sift4G	Benign	0.64	T;T
Polyphen		0.99	D;B
Vest4		0.38
MutPred		0.11		Loss of stability (P = 0.0897);.;
MVP		0.055
MPC		0.064
ClinPred		0.11	T
GERP RS		-3.4
Varity_R		0.050
gMVP		0.073

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-52000157;