19-51530720-C-T

Variant summary

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

The NM_001245.7(SIGLEC6):c.667G>A(p.Gly223Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: SIGLEC6 NM_001245.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.34

Genes affected

SIGLEC6 (HGNC:10875): (sialic acid binding Ig like lectin 6) This gene encodes a member of the SIGLEC (sialic acid binding immunoglobulin-like lectin) family of proteins. The encoded transmembrane receptor binds sialyl-TN glycans and leptin. Placental expression of the encoded protein is upregulated in preeclampsia. [provided by RefSeq, Jul 2016]

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=0.04380402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC6	NM_001245.7	c.667G>A	p.Gly223Ser	missense_variant	3/8	ENST00000425629.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC6	ENST00000425629.8	c.667G>A	p.Gly223Ser	missense_variant	3/8	2	NM_001245.7	P2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 250690 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135648

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000496 AC: 725 AN: 1461782 Hom.: 0 Cov.: 34 AF XY: 0.000476 AC XY: 346 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000617

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74436

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000308 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000382

EpiControl AF: 0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2022

The c.667G>A (p.G223S) alteration is located in exon 3 (coding exon 3) of the SIGLEC6 gene. This alteration results from a G to A substitution at nucleotide position 667, causing the glycine (G) at amino acid position 223 to be replaced by a serine (S). 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	-0.53	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	2.0
Dann	Benign	0.90
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.55	T;T;T;T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.044	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
REVEL	Benign	0.036
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.66	P;.;.;P;B;B
Vest4		0.17
MVP		0.11
MPC		0.57
ClinPred		0.087	T
GERP RS		1.2
Varity_R		0.066
gMVP		0.27

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: rs186522588; hg19: chr19-52033974; COSMIC: COSV104660983; COSMIC: COSV104660983;