Genetic Variant NM_014442.3:c.*1539T>C (chr19-51450840-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014442.3(SIGLEC8):c.*1539T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,152 control chromosomes in the GnomAD database, including 3,050 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 3050 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

SIGLEC8
NM_014442.3 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.874

Publications

4 publications found

Variant links:

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]

SIGLEC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
SIGLEC8	NM_014442.3 link	c.*1539T>C	downstream_gene_variant	ENST00000321424.7	NP_055257.2	Q9NYZ4-1
SIGLEC8	NM_001363548.1 link	c.*1539T>C	downstream_gene_variant		NP_001350477.1
SIGLEC8	XM_011526734.3 link	c.*1539T>C	downstream_gene_variant		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7 link	c.*1539T>C		downstream_gene_variant		1	NM_014442.3	ENSP00000321077.2		Q9NYZ4-1
SIGLEC8	ENST00000430817.5 link	c.*297T>C		downstream_gene_variant		2		ENSP00000389142.1		C9JT30

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28398

AN:

152032

Hom.:

3051

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.467

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.212

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.174

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.187

AC:

28395

AN:

152150

Hom.:

3050

Cov.:

AF XY:

0.189

AC XY:

14029

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.149

AC:

6179

AN:

41514

American (AMR)

AF:

0.148

AC:

2256

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

484

AN:

3472

East Asian (EAS)

AF:

0.468

AC:

2416

AN:

5166

South Asian (SAS)

AF:

0.227

AC:

1095

AN:

4822

European-Finnish (FIN)

AF:

0.212

AC:

2241

AN:

10586

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.193

AC:

13116

AN:

67978

Other (OTH)

AF:

0.174

AC:

368

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1162

2325

3487

4650

5812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

318

636

954

1272

1590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.188

Hom.:

11404

Bravo

AF:

0.180

Asia WGS

AF:

0.316

AC:

1098

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.0

(source)

DANN

Benign

0.49

PhyloP100

-0.87

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over