12-69350159-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000239.3(LYZ):c.188A>G(p.Tyr63Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYZ NM_000239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.514

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a disulfide_bond (size 86) in uniprot entity LYSC_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000239.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYZ	NM_000239.3	c.188A>G	p.Tyr63Cys	missense_variant	2/4	ENST00000261267.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYZ	ENST00000261267.7	c.188A>G	p.Tyr63Cys	missense_variant	2/4	1	NM_000239.3	P1
LYZ	ENST00000549690.1	c.188A>G	p.Tyr63Cys	missense_variant	2/3	2
LYZ	ENST00000548839.1	c.188A>G	p.Tyr63Cys	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the LYZ protein (p.Tyr63Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LYZ-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Pathogenic	3.5	M;.;.
MutationTaster	Benign	0.57	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.42
MutPred		0.53		Gain of catalytic residue at R68 (P = 2e-04);Gain of catalytic residue at R68 (P = 2e-04);Gain of catalytic residue at R68 (P = 2e-04);
MVP		0.93
MPC		0.92
ClinPred		0.79	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-69743939;