19-51531295-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001245.7(SIGLEC6):c.292G>T(p.Asp98Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,190 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (134 hom.)
• Consequence: SIGLEC6 NM_001245.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0130

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009081155).
• BP6: Variant 19-51531295-C-A is Benign according to our data. Variant chr19-51531295-C-A is described in ClinVar as [Benign]. Clinvar id is 789352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.011 (16093/1461868) while in subpopulation MID AF= 0.0251 (145/5768). AF 95% confidence interval is 0.0218. There are 134 homozygotes in gnomad4_exome. There are 7981 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC6	NM_001245.7	c.292G>T	p.Asp98Tyr	missense_variant	2/8	ENST00000425629.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC6	ENST00000425629.8	c.292G>T	p.Asp98Tyr	missense_variant	2/8	2	NM_001245.7	P2

Frequencies

GnomAD3 genomes AF: 0.00824 AC: 1254 AN: 152204 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00881 AC: 2209 AN: 250838 Hom.: 20 AF XY: 0.00944 AC XY: 1282 AN XY: 135768

Gnomad AFR exome AF: 0.00157

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00673

Gnomad FIN exome AF: 0.00651

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0110 AC: 16093 AN: 1461868 Hom.: 134 Cov.: 36 AF XY: 0.0110 AC XY: 7981 AN XY: 727246

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.0252

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00647

Gnomad4 FIN exome AF: 0.00784

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.00821 AC: 1250 AN: 152322 Hom.: 7 Cov.: 32 AF XY: 0.00780 AC XY: 581 AN XY: 74480

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00715

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0127 Hom.: 29

Bravo AF: 0.00830

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.0125 AC: 107

ExAC AF: 0.00857 AC: 1041

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0153

EpiControl AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	SIGLEC6: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
MetaRNN	Benign	0.0091	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
REVEL	Benign	0.13
Sift4G	Uncertain	0.024	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;D
Vest4		0.31
MVP		0.67
MPC		0.69
ClinPred		0.12	T
GERP RS		0.74
Varity_R		0.69
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62617068; hg19: chr19-52034549; COSMIC: COSV99063963; COSMIC: COSV99063963;