19-51497366-G-C

Position:

• chr19-51497366-G-C

Variant summary

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

The ENST00000291707.8(SIGLEC12):​c.1485C>G​(p.Phe495Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGLEC12 ENST00000291707.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0400

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC12	NM_053003.4	c.1485C>G	p.Phe495Leu	missense_variant	6/8	ENST00000291707.8	NP_443729.1
SIGLEC12	NM_033329.2	c.1131C>G	p.Phe377Leu	missense_variant	5/7		NP_201586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGLEC12	ENST00000291707.8	c.1485C>G	p.Phe495Leu	missense_variant	6/8	1	NM_053003.4	ENSP00000291707	P1
SIGLEC12	ENST00000596742.1	c.*700C>G		3_prime_UTR_variant, NMD_transcript_variant	6/8	1		ENSP00000469791
SIGLEC12	ENST00000598614.1	c.1131C>G	p.Phe377Leu	missense_variant	5/7	5		ENSP00000472873

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

The c.1485C>G (p.F495L) alteration is located in exon 6 (coding exon 6) of the SIGLEC12 gene. This alteration results from a C to G substitution at nucleotide position 1485, causing the phenylalanine (F) at amino acid position 495 to be replaced by a leucine (L). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.9
DANN	Benign	0.27
DEOGEN2	Benign	0.0016	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.10	N;.
REVEL	Benign	0.0030
Sift	Benign	0.81	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0080	B;B
Vest4		0.057
MutPred		0.39		Gain of sheet (P = 0.0477);.;
MVP		0.12
MPC		0.051
ClinPred		0.025	T
GERP RS		-0.80
Varity_R		0.049
gMVP		0.059

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -17

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: chr19-52000620;