Genetic Variant LGALS3:p.Thr98Pro (chr14-55138318-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002306.4(LGALS3):c.292A>C(p.Thr98Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,611,258 control chromosomes in the GnomAD database, including 175,477 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T98T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.56 ( 26584 hom., cov: 32)

Exomes 𝑓: 0.44 ( 148893 hom. )

Consequence

LGALS3
NM_002306.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

86 publications found

Variant links:

Genes affected

LGALS3 (HGNC:6563): (galectin 3) This gene encodes a member of the galectin family of carbohydrate binding proteins. Members of this protein family have an affinity for beta-galactosides. The encoded protein is characterized by an N-terminal proline-rich tandem repeat domain and a single C-terminal carbohydrate recognition domain. This protein can self-associate through the N-terminal domain allowing it to bind to multivalent saccharide ligands. This protein localizes to the extracellular matrix, the cytoplasm and the nucleus. This protein plays a role in numerous cellular functions including apoptosis, innate immunity, cell adhesion and T-cell regulation. The protein exhibits antimicrobial activity against bacteria and fungi. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2014]

LGALS3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.901192E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGALS3	NM_002306.4 link	c.292A>C	p.Thr98Pro	missense_variant	Exon 3 of 6	ENST00000254301.14	NP_002297.2	P17931A0A024R693
LGALS3	NM_001357678.2 link	c.334A>C	p.Thr112Pro	missense_variant	Exon 4 of 7		NP_001344607.1
LGALS3	NR_003225.2 link	n.1336A>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGALS3	ENST00000254301.14 link	c.292A>C	p.Thr98Pro	missense_variant	Exon 3 of 6	1	NM_002306.4	ENSP00000254301.9		P17931

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84503

AN:

151980

Hom.:

26525

Cov.:

show subpopulations

Gnomad AFR

AF:

0.871

Gnomad AMI

AF:

0.437

Gnomad AMR

AF:

0.407

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.471

Gnomad FIN

AF:

0.537

Gnomad MID

AF:

0.401

Gnomad NFE

AF:

0.432

Gnomad OTH

AF:

0.486

GnomAD2 exomes

AF:

0.446

AC:

107637

AN:

241330

AF XY:

0.443

show subpopulations

Gnomad AFR exome

AF:

0.877

Gnomad AMR exome

AF:

0.307

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.389

Gnomad FIN exome

AF:

0.527

Gnomad NFE exome

AF:

0.428

Gnomad OTH exome

AF:

0.428

GnomAD4 exome

AF:

0.445

AC:

648954

AN:

1459160

Hom.:

148893

Cov.:

AF XY:

0.444

AC XY:

322025

AN XY:

725928

show subpopulations

African (AFR)

AF:

0.887

AC:

29668

AN:

33436

American (AMR)

AF:

0.319

AC:

14213

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

9848

AN:

26098

East Asian (EAS)

AF:

0.431

AC:

17108

AN:

39672

South Asian (SAS)

AF:

0.473

AC:

40797

AN:

86200

European-Finnish (FIN)

AF:

0.524

AC:

27259

AN:

52012

Middle Eastern (MID)

AF:

0.374

AC:

2156

AN:

5762

European-Non Finnish (NFE)

AF:

0.432

AC:

480257

AN:

1111162

Other (OTH)

AF:

0.458

AC:

27648

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

18446

36893

55339

73786

92232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14804

29608

44412

59216

74020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.556

AC:

84622

AN:

152098

Hom.:

26584

Cov.:

AF XY:

0.554

AC XY:

41233

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.871

AC:

36181

AN:

41534

American (AMR)

AF:

0.407

AC:

6220

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

1303

AN:

3470

East Asian (EAS)

AF:

0.405

AC:

2087

AN:

5156

South Asian (SAS)

AF:

0.472

AC:

2277

AN:

4828

European-Finnish (FIN)

AF:

0.537

AC:

5674

AN:

10570

Middle Eastern (MID)

AF:

0.401

AC:

118

AN:

294

European-Non Finnish (NFE)

AF:

0.432

AC:

29337

AN:

67934

Other (OTH)

AF:

0.487

AC:

1028

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1679

3358

5037

6716

8395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

690

1380

2070

2760

3450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.443

Hom.:

28857

Bravo

AF:

0.555

TwinsUK

AF:

0.434

AC:

1610

ALSPAC

AF:

0.430

AC:

1657

ESP6500AA

AF:

0.858

AC:

2923

ESP6500EA

AF:

0.467

AC:

3644

ExAC

AF:

0.450

AC:

53054

Asia WGS

AF:

0.488

AC:

1694

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.8

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.064

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.019

T;T

MetaRNN

Benign

9.9e-7

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.9

N;.

PhyloP100

1.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

4.1

N;N

REVEL

Benign

0.053

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.049

MPC

0.077

ClinPred

0.00026

GERP RS

3.3

Varity_R

0.054

gMVP

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over