17-27640673-A-C

Position:

• chr17-27640673-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_009587.3(LGALS9):​c.233A>C​(p.Gln78Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,880 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LGALS9 NM_009587.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.49

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]

ENSG00000266728 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGALS9	NM_009587.3	c.233A>C	p.Gln78Pro	missense_variant	3/11	ENST00000395473.7	NP_033665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGALS9	ENST00000395473.7	c.233A>C	p.Gln78Pro	missense_variant	3/11	1	NM_009587.3	ENSP00000378856.2
ENSG00000266728	ENST00000584605.5	n.*217A>C		non_coding_transcript_exon_variant	3/3	2		ENSP00000463557.1
ENSG00000266728	ENST00000584605.5	n.*217A>C		3_prime_UTR_variant	3/3	2		ENSP00000463557.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: 0.00000180

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2023

The c.233A>C (p.Q78P) alteration is located in exon 3 (coding exon 3) of the LGALS9 gene. This alteration results from a A to C substitution at nucleotide position 233, causing the glutamine (Q) at amino acid position 78 to be replaced by a proline (P). 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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D;T;D
M_CAP	Benign	0.0086	T
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.2	M;M;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.0	D;D;D;.
REVEL	Benign	0.18
Sift	Uncertain	0.011	D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.93	P;.;.;.
Vest4		0.62
MutPred		0.69		Loss of catalytic residue at Q78 (P = 0.0751);Loss of catalytic residue at Q78 (P = 0.0751);Loss of catalytic residue at Q78 (P = 0.0751);Loss of catalytic residue at Q78 (P = 0.0751);
MVP		0.41
MPC		1.0
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.91
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-25967699;