rs3746638

Positions:

• chr20-3694686-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023068.4(SIGLEC1):​c.2921C>T​(p.Ala974Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,613,248 control chromosomes in the GnomAD database, including 226,070 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.52 (21178 hom., cov: 33)
  • Exomes 𝑓: 0.53 (204892 hom.)
• Consequence: SIGLEC1 NM_023068.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.804

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8835827E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC1	NM_023068.4	c.2921C>T	p.Ala974Val	missense_variant	12/22	ENST00000344754.6
SIGLEC1	NM_001367089.1	c.2921C>T	p.Ala974Val	missense_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC1	ENST00000344754.6	c.2921C>T	p.Ala974Val	missense_variant	12/22	1	NM_023068.4	P2
SIGLEC1	ENST00000707083.1	c.2921C>T	p.Ala974Val	missense_variant	11/20			A2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79503 AN: 152034 Hom.: 21165 Cov.: 33

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.525

GnomAD3 exomes AF: 0.575 AC: 144294 AN: 250744 Hom.: 42543 AF XY: 0.573 AC XY: 77727 AN XY: 135570

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.684

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.761

Gnomad SAS exome AF: 0.628

Gnomad FIN exome AF: 0.619

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.526 AC: 768539 AN: 1461096 Hom.: 204892 Cov.: 58 AF XY: 0.529 AC XY: 384603 AN XY: 726842

Gnomad4 AFR exome AF: 0.444

Gnomad4 AMR exome AF: 0.675

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.702

Gnomad4 SAS exome AF: 0.626

Gnomad4 FIN exome AF: 0.608

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.532

GnomAD4 genome AF: 0.523 AC: 79551 AN: 152152 Hom.: 21178 Cov.: 33 AF XY: 0.534 AC XY: 39740 AN XY: 74386

Gnomad4 AFR AF: 0.456

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.749

Gnomad4 SAS AF: 0.644

Gnomad4 FIN AF: 0.622

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.521

Alfa AF: 0.518 Hom.: 38401

Bravo AF: 0.516

TwinsUK AF: 0.501 AC: 1857

ALSPAC AF: 0.497 AC: 1915

ESP6500AA AF: 0.445 AC: 1961

ESP6500EA AF: 0.509 AC: 4380

ExAC AF: 0.567 AC: 68859

Asia WGS AF: 0.652 AC: 2271 AN: 3478

EpiCase AF: 0.509

EpiControl AF: 0.507

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.056
Sift	Benign	0.12	T
Sift4G	Uncertain	0.028	D
Polyphen		0.20	B
Vest4		0.029
MPC		0.13
ClinPred		0.021	T
GERP RS		2.6
Varity_R		0.076
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs3746638; hg19: chr20-3675333; COSMIC: COSV52465019; COSMIC: COSV52465019;