NM_023068.4:c.661G>A

Variant names:

• chr20-3705789-C-T
• rs6037651
• NM_023068.4:c.661G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023068.4(SIGLEC1):​c.661G>A​(p.Val221Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,613,110 control chromosomes in the GnomAD database, including 307,700 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. V221L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.64 (32017 hom., cov: 34)
  • Exomes 𝑓: 0.61 (275683 hom.)
• Consequence: SIGLEC1 NM_023068.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.515
• Publications: 36 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1461643E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023068.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC1	NM_023068.4	MANE Select	c.661G>A	p.Val221Met	missense	Exon 4 of 22	NP_075556.1
	SIGLEC1	NM_001367089.1		c.661G>A	p.Val221Met	missense	Exon 3 of 20	NP_001354018.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC1	ENST00000344754.6	TSL:1 MANE Select	c.661G>A	p.Val221Met	missense	Exon 4 of 22	ENSP00000341141.4
	SIGLEC1	ENST00000707083.1		c.661G>A	p.Val221Met	missense	Exon 3 of 20	ENSP00000516734.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 98017 AN: 152064 Hom.: 31985 Cov.: 34

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.630

GnomAD2 exomes AF: 0.654 AC: 163781 AN: 250580 AF XY: 0.655

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.670

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.750

Gnomad FIN exome AF: 0.666

Gnomad NFE exome AF: 0.600

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.612 AC: 893894 AN: 1460928 Hom.: 275683 Cov.: 61 AF XY: 0.616 AC XY: 447800 AN XY: 726702

African (AFR) AF: 0.731 AC: 24471 AN: 33470

American (AMR) AF: 0.662 AC: 29605 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 15635 AN: 26122

East Asian (EAS) AF: 0.690 AC: 27384 AN: 39676

South Asian (SAS) AF: 0.752 AC: 64828 AN: 86232

European-Finnish (FIN) AF: 0.660 AC: 35061 AN: 53134

Middle Eastern (MID) AF: 0.622 AC: 3582 AN: 5762

European-Non Finnish (NFE) AF: 0.590 AC: 655561 AN: 1111452

Other (OTH) AF: 0.626 AC: 37767 AN: 60372

GnomAD4 genome AF: 0.645 AC: 98100 AN: 152182 Hom.: 32017 Cov.: 34 AF XY: 0.650 AC XY: 48364 AN XY: 74400

African (AFR) AF: 0.726 AC: 30153 AN: 41524

American (AMR) AF: 0.609 AC: 9311 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2032 AN: 3472

East Asian (EAS) AF: 0.734 AC: 3790 AN: 5162

South Asian (SAS) AF: 0.761 AC: 3675 AN: 4832

European-Finnish (FIN) AF: 0.663 AC: 7025 AN: 10592

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40304 AN: 67980

Other (OTH) AF: 0.623 AC: 1317 AN: 2114

Alfa AF: 0.611 Hom.: 108049

Bravo AF: 0.641

TwinsUK AF: 0.599 AC: 2220

ALSPAC AF: 0.586 AC: 2259

ESP6500AA AF: 0.713 AC: 3143

ESP6500EA AF: 0.594 AC: 5108

ExAC AF: 0.656 AC: 79698

Asia WGS AF: 0.691 AC: 2405 AN: 3478

EpiCase AF: 0.594

EpiControl AF: 0.590

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.6
DANN	Benign	0.90
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.52
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.030
Sift	Benign	0.22	T
Sift4G	Benign	0.23	T
Polyphen		0.20	B
Vest4		0.037
MPC		0.17
ClinPred		0.0037	T
GERP RS		0.33
Varity_R		0.044
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6037651; hg19: chr20-3686436; COSMIC: COSV52460057;