dbSNP rs39711: SIGLEC8:c.*775A>G (chr19-51451604-T-C) – 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.*775A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,080 control chromosomes in the GnomAD database, including 10,449 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 0.34 ( 10449 hom., cov: 32)

Exomes 𝑓: 0.50 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

SIGLEC8
NM_014442.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.575

Publications

5 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=-0.95).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC8	NM_014442.3 link	c.*775A>G	3_prime_UTR_variant	Exon 7 of 7	ENST00000321424.7	NP_055257.2	Q9NYZ4-1
SIGLEC8	NM_001363548.1 link	c.*775A>G	3_prime_UTR_variant	Exon 6 of 6		NP_001350477.1
SIGLEC8	XM_011526734.3 link	c.*775A>G	3_prime_UTR_variant	Exon 7 of 7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7 link	c.*775A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_014442.3	ENSP00000321077.2		Q9NYZ4-1
SIGLEC8	ENST00000430817.5 link	c.*42-509A>G		intron_variant	Intron 5 of 5	2		ENSP00000389142.1		C9JT30

Frequencies

GnomAD3 genomes

AF:

0.344

AC:

52347

AN:

151962

Hom.:

10419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.528

Gnomad AMI

AF:

0.264

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.554

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.335

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.319

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.611

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)

AF:

0.750

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.556

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0102767), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.345

AC:

52425

AN:

152080

Hom.:

10449

Cov.:

AF XY:

0.347

AC XY:

25810

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.528

AC:

21908

AN:

41456

American (AMR)

AF:

0.252

AC:

3854

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

666

AN:

3468

East Asian (EAS)

AF:

0.555

AC:

2863

AN:

5160

South Asian (SAS)

AF:

0.294

AC:

1419

AN:

4820

European-Finnish (FIN)

AF:

0.335

AC:

3549

AN:

10584

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.252

AC:

17164

AN:

67984

Other (OTH)

AF:

0.322

AC:

680

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1651

3302

4954

6605

8256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

500

1000

1500

2000

2500

<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:

0.278

Hom.:

28616

Bravo

AF:

0.345

Asia WGS

AF:

0.445

AC:

1550

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.6

(source)

DANN

Benign

0.77

PhyloP100

-0.57

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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