19-51497379-A-G

Variant names:

• chr19-51497379-A-G
• rs1990270346
• NM_053003.4:c.1472T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053003.4(SIGLEC12):​c.1472T>C​(p.Val491Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,122 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SIGLEC12 NM_053003.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08427358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC12	NM_053003.4	c.1472T>C	p.Val491Ala	missense_variant	Exon 6 of 8	ENST00000291707.8	NP_443729.1
SIGLEC12	NM_033329.2	c.1118T>C	p.Val373Ala	missense_variant	Exon 5 of 7		NP_201586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC12	ENST00000291707.8	c.1472T>C	p.Val491Ala	missense_variant	Exon 6 of 8	1	NM_053003.4	ENSP00000291707.3
SIGLEC12	ENST00000596742.1	n.*687T>C		non_coding_transcript_exon_variant	Exon 6 of 8	1		ENSP00000469791.1
SIGLEC12	ENST00000596742.1	n.*687T>C		3_prime_UTR_variant	Exon 6 of 8	1		ENSP00000469791.1
SIGLEC12	ENST00000598614.1	c.1118T>C	p.Val373Ala	missense_variant	Exon 5 of 7	5		ENSP00000472873.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460952 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 726846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1472T>C (p.V491A) alteration is located in exon 6 (coding exon 6) of the SIGLEC12 gene. This alteration results from a T to C substitution at nucleotide position 1472, causing the valine (V) at amino acid position 491 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.0
DANN	Benign	0.79
DEOGEN2	Benign	0.0078	T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.21	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.016
Sift	Benign	0.22	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.052	B;B
Vest4		0.088
MutPred		0.41		Gain of sheet (P = 0.0266);.;
MVP		0.34
MPC		0.051
ClinPred		0.076	T
GERP RS		1.7
Varity_R		0.061
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs1990270346; hg19: chr19-52000633;