20-3691399-C-T

Position:

• chr20-3691399-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Moderate BP6_Moderate BS2

The NM_023068.4(SIGLEC1):​c.4532G>A​(p.Cys1511Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00418 in 1,613,400 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (25 hom.)
• Consequence: SIGLEC1 NM_023068.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.39

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 -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.20969489).
• BP6: Variant 20-3691399-C-T is Benign according to our data. Variant chr20-3691399-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2652176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC1	NM_023068.4	c.4532G>A	p.Cys1511Tyr	missense_variant	18/22	ENST00000344754.6
SIGLEC1	NM_001367089.1	c.4532G>A	p.Cys1511Tyr	missense_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC1	ENST00000344754.6	c.4532G>A	p.Cys1511Tyr	missense_variant	18/22	1	NM_023068.4	P2
SIGLEC1	ENST00000707083.1	c.4532G>A	p.Cys1511Tyr	missense_variant	17/20			A2
SIGLEC1	ENST00000419548.4	c.974G>A	p.Cys325Tyr	missense_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 399 AN: 152248 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00248 AC: 623 AN: 250734 Hom.: 1 AF XY: 0.00245 AC XY: 332 AN XY: 135740

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00434 AC: 6348 AN: 1461034 Hom.: 25 Cov.: 33 AF XY: 0.00430 AC XY: 3123 AN XY: 726852

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000399

Gnomad4 NFE exome AF: 0.00542

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152366 Hom.: 3 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74520

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00402 Hom.: 3

Bravo AF: 0.00258

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00251 AC: 305

EpiCase AF: 0.00436

EpiControl AF: 0.00492

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

SIGLEC1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.93
MPC		0.70
ClinPred		0.18	T
GERP RS		5.3
Varity_R		0.95
gMVP		0.98

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: rs143489222; hg19: chr20-3672046;