17-27645347-A-T

Position:

• chr17-27645347-A-T

Variant summary

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

The NM_009587.3(LGALS9):​c.574A>T​(p.Ile192Phe) variant causes a missense, splice region 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. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: LGALS9 NM_009587.3 missense, splice_region
• Scores: Splicing: ADA: 0.0007597
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.624

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=0.047480404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGALS9	NM_009587.3	c.574A>T	p.Ile192Phe	missense_variant, splice_region_variant	6/11	ENST00000395473.7	NP_033665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGALS9	ENST00000395473.7	c.574A>T	p.Ile192Phe	missense_variant, splice_region_variant	6/11	1	NM_009587.3	ENSP00000378856	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

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

Oct 24, 2023

The c.574A>T (p.I192F) alteration is located in exon 6 (coding exon 6) of the LGALS9 gene. This alteration results from a A to T substitution at nucleotide position 574, causing the isoleucine (I) at amino acid position 192 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.65
DANN	Benign	0.85
DEOGEN2	Benign	0.14	T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.43	T;T;T;T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.047	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Benign	0.018
Sift	Benign	0.17	T;T;T;.
Sift4G	Benign	0.64	T;T;T;D
Polyphen		0.43	B;.;.;.
Vest4		0.14
MutPred		0.20		Loss of glycosylation at T193 (P = 0.1075);.;.;.;
MVP		0.092
MPC		1.9
ClinPred		0.15	T
GERP RS		-4.5
Varity_R		0.065
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00076
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.030		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: chr17-25972373;