19-49950094-G-A

Variant names:

• chr19-49950094-G-A
• rs201942673
• NM_052884.3:c.1973C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052884.3(SIGLEC11):​c.1973C>T​(p.Ala658Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,610,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SIGLEC11 NM_052884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.00

Genes affected

SIGLEC11 (HGNC:15622): (sialic acid binding Ig like lectin 11) This gene encodes a member of the sialic acid-binding immunoglobulin-like lectin family. These cell surface lectins are characterized by structural motifs in the immunoglobulin (Ig)-like domains and sialic acid recognition sites in the first Ig V set domain. This family member mediates anti-inflammatory and immunosuppressive signaling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ENSG00000269179 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013049662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC11	NM_052884.3	c.1973C>T	p.Ala658Val	missense_variant	Exon 11 of 11	ENST00000447370.6	NP_443116.2
SIGLEC11	NM_001135163.1	c.1685C>T	p.Ala562Val	missense_variant	Exon 10 of 10		NP_001128635.1
SIGLEC11	XM_005258476.4	c.1997C>T	p.Ala666Val	missense_variant	Exon 10 of 10		XP_005258533.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC11	ENST00000447370.6	c.1973C>T	p.Ala658Val	missense_variant	Exon 11 of 11	1	NM_052884.3	ENSP00000412361.2
ENSG00000269179	ENST00000451973.1	n.*77+1797C>T		intron_variant	Intron 2 of 2	2		ENSP00000391489.1

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151746 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000730

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000164 AC: 41 AN: 249242 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 134882

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000711

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.000421

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1458862 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 725664

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.0000991

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151864 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74232

Gnomad4 AFR AF: 0.0000728

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000110

EpiControl AF: 0.0000596

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1973C>T (p.A658V) alteration is located in exon 11 (coding exon 11) of the SIGLEC11 gene. This alteration results from a C to T substitution at nucleotide position 1973, causing the alanine (A) at amino acid position 658 to be replaced by a valine (V). 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	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.022
DANN	Benign	0.75
DEOGEN2	Benign	0.0049	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.11	T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.073
Sift	Benign	0.11	T;.
Sift4G	Uncertain	0.022	D;T
Polyphen		0.45	B;D
Vest4		0.066
MVP		0.12
MPC		0.015
ClinPred		0.029	T
GERP RS		-7.9
Varity_R		0.029
gMVP		0.063

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: rs201942673; hg19: chr19-50453351;