17-27643562-C-A

Variant names:

• chr17-27643562-C-A
• rs756309515
• NM_009587.3:c.482C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_009587.3(LGALS9):​c.482C>A​(p.Thr161Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T161M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LGALS9 NM_009587.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.62

Genes affected

LGALS9 (HGNC:6570): (galectin 9) The galectins are a family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. The protein encoded by this gene is an S-type lectin. It is overexpressed in Hodgkin's disease tissue and might participate in the interaction between the H&RS cells with their surrounding cells and might thus play a role in the pathogenesis of this disease and/or its associated immunodeficiency. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03853163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGALS9	NM_009587.3	c.482C>A	p.Thr161Lys	missense_variant	Exon 5 of 11	ENST00000395473.7	NP_033665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGALS9	ENST00000395473.7	c.482C>A	p.Thr161Lys	missense_variant	Exon 5 of 11	1	NM_009587.3	ENSP00000378856.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459588 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726118

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.482C>A (p.T161K) alteration is located in exon 5 (coding exon 5) of the LGALS9 gene. This alteration results from a C to A substitution at nucleotide position 482, causing the threonine (T) at amino acid position 161 to be replaced by a lysine (K). 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	Benign	0.091
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.035
DANN	Benign	0.47
DEOGEN2	Benign	0.091	T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.24	T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.039	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.96	N;.;.
REVEL	Benign	0.064
Sift	Benign	0.94	T;.;.
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0060	B;.;.
Vest4		0.13
MutPred		0.32		Gain of methylation at T161 (P = 0.0029);.;.;
MVP		0.14
MPC		1.5
ClinPred		0.029	T
GERP RS		-3.2
Varity_R		0.038
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs756309515; hg19: chr17-25970588;