20-3694851-T-C

Variant names:

• chr20-3694851-T-C
• rs709012
• NM_023068.4:c.2756A>G

Variant summary

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

The NM_023068.4(SIGLEC1):​c.2756A>G​(p.His919Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 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. H919P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SIGLEC1 NM_023068.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92

Genes affected

SIGLEC1 (HGNC:11127): (sialic acid binding Ig like lectin 1) This gene encodes a member of the immunoglobulin superfamily. The encoded protein is a lectin-like adhesion molecule that binds glycoconjugate ligands on cell surfaces in a sialic acid-dependent manner. It is a type I transmembrane protein expressed only by a subpopulation of macrophages and is involved in mediating cell-cell interactions. The protein plays an important role in multiple human diseases and bacterial and viral infections has been shown to enhance SARS-CoV-2 infection. [provided by RefSeq, Dec 2021]

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 rank	MANE	Protein	UniProt
SIGLEC1	NM_023068.4	c.2756A>G	p.His919Arg	missense_variant	Exon 12 of 22	ENST00000344754.6	NP_075556.1
SIGLEC1	NM_001367089.1	c.2756A>G	p.His919Arg	missense_variant	Exon 11 of 20		NP_001354018.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC1	ENST00000344754.6	c.2756A>G	p.His919Arg	missense_variant	Exon 12 of 22	1	NM_023068.4	ENSP00000341141.4
SIGLEC1	ENST00000707083.1	c.2756A>G	p.His919Arg	missense_variant	Exon 11 of 20			ENSP00000516734.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461080 Hom.: 0 Cov.: 52 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: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.050	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.067
Sift	Benign	0.033	D
Sift4G	Uncertain	0.046	D
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.68		Gain of MoRF binding (P = 0.0553);
MVP		0.35
MPC		0.13
ClinPred		0.30	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs709012; hg19: chr20-3675498;