19-51643805-T-G

Variant names:

• chr19-51643805-T-G
• rs766785830
• NM_001098612.3:c.986A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001098612.3(SIGLEC14):​c.986A>C​(p.His329Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,385,556 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H329L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000022 (1 hom.)
• Consequence: SIGLEC14 NM_001098612.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0840
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2843358).

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.986A>C	p.His329Pro	missense	Exon 5 of 7	NP_001092082.1	Q08ET2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC14	ENST00000360844.7	TSL:1 MANE Select	c.986A>C	p.His329Pro	missense	Exon 5 of 7	ENSP00000354090.5	Q08ET2
	SIGLEC14	ENST00000533866.1	TSL:4	n.333A>C		non_coding_transcript_exon	Exon 2 of 5
	SIGLEC5	ENST00000534261.4	TSL:5	n.69+1672A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1385556 Hom.: 1 Cov.: 33 AF XY: 0.00000437 AC XY: 3 AN XY: 687166

African (AFR) AF: 0.00 AC: 0 AN: 30834

American (AMR) AF: 0.00 AC: 0 AN: 43094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24696

East Asian (EAS) AF: 0.00 AC: 0 AN: 25848

South Asian (SAS) AF: 0.00 AC: 0 AN: 77838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000280 AC: 3 AN: 1071206

Other (OTH) AF: 0.00 AC: 0 AN: 56752

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.084
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.14
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.042	D
Polyphen		0.82	P
Vest4		0.43
MutPred		0.55		Loss of catalytic residue at H329 (P = 0.0363)
MVP		0.19
MPC		0.54
ClinPred		0.86	D
GERP RS		3.1
Varity_R		0.44
gMVP		0.66
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs766785830; hg19: chr19-52147058;