19-51457463-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014442.3(SIGLEC8):c.731C>T(p.Ser244Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,613,622 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense, splice_region
• Scores: Splicing: ADA: 0.2457
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.533

Genes affected

SIGLEC8 (HGNC:10877): (sialic acid binding Ig like lectin 8) Sialic acid-binding immunoglobulin (Ig)-like lectins, or SIGLECs (e.g., CD33 (MIM 159590)), are a family of type 1 transmembrane proteins each having a unique expression pattern, mostly in hemopoietic cells. SIGLEC8 is a member of the CD33-like subgroup of SIGLECs, which are localized to 19q13.3-q13.4 and have 2 conserved cytoplasmic tyrosine-based motifs: an immunoreceptor tyrosine-based inhibitory motif, or ITIM (see MIM 604964), and a motif homologous to one identified in signaling lymphocyte activation molecule (SLAM; MIM 603492) that mediates an association with SLAM-associated protein (SAP; MIM 300490) (summarized by Foussias et al., 2000 [PubMed 11095983]).[supplied by OMIM, May 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013482302).
• BP6: Variant 19-51457463-G-A is Benign according to our data. Variant chr19-51457463-G-A is described in ClinVar as [Benign]. Clinvar id is 716482.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGLEC8	NM_014442.3	c.731C>T	p.Ser244Phe	missense_variant, splice_region_variant	2/7	ENST00000321424.7
SIGLEC8	XM_011526734.3	c.698C>T	p.Ser233Phe	missense_variant, splice_region_variant	2/7
SIGLEC8	NM_001363548.1	c.455-232C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.731C>T	p.Ser244Phe	missense_variant, splice_region_variant	2/7	1	NM_014442.3	P1
SIGLEC8	ENST00000340550.5	c.455-232C>T		intron_variant		1
SIGLEC8	ENST00000430817.5	c.454+471C>T		intron_variant		2
SIGLEC8	ENST00000597352.1	n.347C>T		splice_region_variant, non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152132 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00983

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000706 AC: 177 AN: 250884 Hom.: 0 AF XY: 0.000531 AC XY: 72 AN XY: 135596

Gnomad AFR exome AF: 0.00960

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000270 AC: 395 AN: 1461372 Hom.: 3 Cov.: 32 AF XY: 0.000213 AC XY: 155 AN XY: 727026

Gnomad4 AFR exome AF: 0.00887

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152250 Hom.: 2 Cov.: 31 AF XY: 0.00277 AC XY: 206 AN XY: 74444

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000482 Hom.: 1

Bravo AF: 0.00315

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.0051
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	0.97	D;D;N
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.21
MVP		0.76
MPC		0.44
ClinPred		0.095	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.34
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: rs149444610; hg19: chr19-51960717;