Genetic Variant LYZ:p.Thr88Ile (chr12-69350234-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000239.3(LYZ):c.263C>T(p.Thr88Ile) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T88N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LYZ
NM_000239.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Publications

37 publications found

Variant links:

Genes affected

LYZ (HGNC:6740): (lysozyme) This gene encodes human lysozyme, whose natural substrate is the bacterial cell wall peptidoglycan (cleaving the beta[1-4]glycosidic linkages between N-acetylmuramic acid and N-acetylglucosamine). Lysozyme is one of the antimicrobial agents found in human milk, and is also present in spleen, lung, kidney, white blood cells, plasma, saliva, and tears. The protein has antibacterial activity against a number of bacterial species. Missense mutations in this gene have been identified in heritable renal amyloidosis. [provided by RefSeq, Oct 2014]

LYZ Gene-Disease associations (from GenCC):

familial visceral amyloidosis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
ALys amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LYZ links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000239.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4092105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYZ	NM_000239.3 link	c.263C>T	p.Thr88Ile	missense_variant	Exon 2 of 4	ENST00000261267.7	NP_000230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LYZ	ENST00000261267.7 link	c.263C>T	p.Thr88Ile	missense_variant	Exon 2 of 4	1	NM_000239.3	ENSP00000261267.2
LYZ	ENST00000549690.1 link	c.263C>T	p.Thr88Ile	missense_variant	Exon 2 of 3	2		ENSP00000449898.1
LYZ	ENST00000548839.1 link	c.263C>T	p.Thr88Ile	missense_variant	Exon 2 of 2	2		ENSP00000449969.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

1247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

T;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

D;D;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Pathogenic

3.1

M;.;.

PhyloP100

2.8

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Uncertain

0.44

Sift

Benign

0.049

D;D;D

Sift4G

Benign

0.11

T;T;T

Polyphen

0.80

P;.;.

Vest4

0.29

MutPred

0.69

Gain of catalytic residue at T88 (P = 0.001);Gain of catalytic residue at T88 (P = 0.001);Gain of catalytic residue at T88 (P = 0.001);

MVP

0.91

MPC

0.48

ClinPred

0.98

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.75

Mutation Taster

=82/18

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over