Genetic Variant NM_001098612.3:c.1138T>C (chr19-51643547-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001098612.3(SIGLEC14):c.1138T>C(p.Tyr380His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000552 in 1,520,646 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 5 hom., cov: 23)

Exomes 𝑓: 0.00058 ( 125 hom. )

Consequence

SIGLEC14
NM_001098612.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.47

Publications

0 publications found

Variant links:

Genes affected

SIGLEC14 (HGNC:32926): (sialic acid binding Ig like lectin 14) Predicted to enable sialic acid binding activity. Predicted to be involved in cell adhesion. Predicted to be located in ficolin-1-rich granule membrane and tertiary granule membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SIGLEC14 links:

SIGLEC5 (HGNC:10874): (sialic acid binding Ig like lectin 5) This gene encodes a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family. These cell surface lectins are characterized by structural motifs in the immunoglobulin (Ig)-like domains and sialic acid recognition sites in the first Ig V set domain. The encoded protein is a member of the CD33-related subset of Siglecs and inhibits the activation of several cell types including monocytes, macrophages and neutrophils. Binding of group B Streptococcus (GBS) to the encoded protein plays a role in GBS immune evasion. [provided by RefSeq, Feb 2012]

SIGLEC5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12582907).

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098612.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC14	NM_001098612.3	MANE Select	c.1138T>C	p.Tyr380His	missense	Exon 6 of 7	NP_001092082.1	Q08ET2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIGLEC14	ENST00000360844.7	TSL:1 MANE Select	c.1138T>C	p.Tyr380His	missense	Exon 6 of 7	ENSP00000354090.5	Q08ET2
SIGLEC14	ENST00000533866.1	TSL:4	n.485T>C		non_coding_transcript_exon	Exon 3 of 5
SIGLEC5	ENST00000534261.4	TSL:5	n.69+1930T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000279

AC:

AN:

132644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000173

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000493

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000215

AC:

AN:

228400

AF XY:

0.000249

show subpopulations

Gnomad AFR exome

AF:

0.0000714

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000430

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000578

AC:

802

AN:

1387910

Hom.:

125

Cov.:

AF XY:

0.000565

AC XY:

390

AN XY:

689770

show subpopulations

African (AFR)

AF:

0.0000650

AC:

AN:

30758

American (AMR)

AF:

0.0000693

AC:

AN:

43318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25034

East Asian (EAS)

AF:

0.00

AC:

AN:

25554

South Asian (SAS)

AF:

0.00

AC:

AN:

78894

European-Finnish (FIN)

AF:

0.0000405

AC:

AN:

49410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4980

European-Non Finnish (NFE)

AF:

0.000688

AC:

738

AN:

1073328

Other (OTH)

AF:

0.00101

AC:

AN:

56634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000279

AC:

AN:

132736

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

AN XY:

64092

show subpopulations

African (AFR)

AF:

0.000173

AC:

AN:

34726

American (AMR)

AF:

0.00

AC:

AN:

14026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3270

East Asian (EAS)

AF:

0.00

AC:

AN:

2568

South Asian (SAS)

AF:

0.00

AC:

AN:

3744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000494

AC:

AN:

62814

Other (OTH)

AF:

0.00

AC:

AN:

1888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000424

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000378

AC:

ExAC

AF:

0.000310

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

Eigen

Benign

-0.016

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.65

M_CAP

Benign

0.0097

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

3.5

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.6

REVEL

Benign

0.14

Sift

Uncertain

0.010

Sift4G

Benign

0.11

Polyphen

0.90

Vest4

0.47

MVP

0.12

MPC

0.64

ClinPred

0.073

GERP RS

2.6

Varity_R

0.15

gMVP

0.34

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over