19-51145899-G-C

Variant names:

• chr19-51145899-G-C
• rs2092104581
• NM_014385.4:c.805G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014385.4(SIGLEC7):​c.805G>C​(p.Gly269Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SIGLEC7 NM_014385.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

Genes affected

SIGLEC7 (HGNC:10876): (sialic acid binding Ig like lectin 7) Predicted to enable sialic acid binding activity. Predicted to be involved in cell adhesion. Predicted to be integral component of plasma membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC7	NM_014385.4	c.805G>C	p.Gly269Arg	missense_variant	Exon 4 of 7	ENST00000317643.10	NP_055200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC7	ENST00000317643.10	c.805G>C	p.Gly269Arg	missense_variant	Exon 4 of 7	1	NM_014385.4	ENSP00000323328.6
SIGLEC7	ENST00000305628.7	c.526G>C	p.Gly176Arg	missense_variant	Exon 3 of 6	1		ENSP00000306757.6
SIGLEC7	ENST00000600577.1	c.433+3097G>C		intron_variant	Intron 1 of 1	1		ENSP00000472529.1
SIGLEC7	ENST00000536156.5	n.434-1322G>C		intron_variant	Intron 1 of 2	1		ENSP00000437609.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.805G>C (p.G269R) alteration is located in exon 4 (coding exon 4) of the SIGLEC7 gene. This alteration results from a G to C substitution at nucleotide position 805, causing the glycine (G) at amino acid position 269 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.43
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.45
MutPred		0.85		Gain of solvent accessibility (P = 0.0171);.;
MVP		0.77
MPC		0.64
ClinPred		0.96	D
GERP RS		2.3
Varity_R		0.32
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs2092104581; hg19: chr19-51649156;