rs747194891

Variant names:

• chr17-18487686-C-T
• rs747194891
• NM_001040078.3:c.373C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001040078.3(LGALS9C):​c.373C>T​(p.Arg125Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000038 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000018 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: LGALS9C NM_001040078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• Publications: 0 publications found

Genes affected

LGALS9C (HGNC:33874): (galectin 9C) This gene was initially thought to represent a pseudogene of galectin 9; however, this transcript has good exon-intron structure and encodes a predicted protein of the same size as and highly similar to galectin 9. This gene is one of two similar loci on chromosome 17p similar to galectin 9 and now thought to be protein-encoding. This gene is the more telomeric gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040078.3. 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
	LGALS9C	NM_001040078.3	MANE Select	c.373C>T	p.Arg125Cys	missense	Exon 4 of 11	NP_001035167.2	Q6DKI2
	LGALS9C	NM_001438918.1		c.373C>T	p.Arg125Cys	missense	Exon 4 of 11	NP_001425847.1
	LGALS9C	NM_001438919.1		c.373C>T	p.Arg125Cys	missense	Exon 4 of 10	NP_001425848.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGALS9C	ENST00000328114.11	TSL:1 MANE Select	c.373C>T	p.Arg125Cys	missense	Exon 4 of 11	ENSP00000329932.6	Q6DKI2
	LGALS9C	ENST00000892832.1		c.373C>T	p.Arg125Cys	missense	Exon 4 of 11	ENSP00000562891.1
	LGALS9C	ENST00000583322.5	TSL:5	c.373C>T	p.Arg125Cys	missense	Exon 4 of 10	ENSP00000462708.1	J3KSY2

Frequencies

GnomAD3 genomes AF: 0.0000380 AC: 5 AN: 131488 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000357

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000343 AC: 8 AN: 233432 AF XY: 0.0000474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000590

Gnomad OTH exome AF: 0.000177

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000184 AC: 26 AN: 1410218 Hom.: 1 Cov.: 30 AF XY: 0.0000200 AC XY: 14 AN XY: 701222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 43560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39526

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 0.0000206 AC: 22 AN: 1070458

Other (OTH) AF: 0.0000344 AC: 2 AN: 58220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000380 AC: 5 AN: 131488 Hom.: 0 Cov.: 19 AF XY: 0.0000471 AC XY: 3 AN XY: 63726

African (AFR) AF: 0.0000254 AC: 1 AN: 39362

American (AMR) AF: 0.000152 AC: 2 AN: 13158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3082

East Asian (EAS) AF: 0.00 AC: 0 AN: 4666

South Asian (SAS) AF: 0.00 AC: 0 AN: 3898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000357 AC: 2 AN: 55966

Other (OTH) AF: 0.00 AC: 0 AN: 1752

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000334 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.76	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	4.2	H
PhyloP100		1.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.95		Loss of sheet (P = 0.1158)
MVP		0.53
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.88
gMVP		0.80
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747194891; hg19: chr17-18391000;