rs121913548

chr12-69350224-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM1 PM2 PP3

The NM_000239.3(LYZ):c.253G>C(p.Asp85His) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYZ NM_000239.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_000239.3 (LYZ) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYZ	NM_000239.3	c.253G>C	p.Asp85His	missense_variant	2/4	ENST00000261267.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYZ	ENST00000261267.7	c.253G>C	p.Asp85His	missense_variant	2/4	1	NM_000239.3	P1
LYZ	ENST00000549690.1	c.253G>C	p.Asp85His	missense_variant	2/3	2
LYZ	ENST00000548839.1	c.253G>C	p.Asp85His	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.086	T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T;D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.67
MutPred		0.75		Gain of catalytic residue at K87 (P = 0.0011);Gain of catalytic residue at K87 (P = 0.0011);Gain of catalytic residue at K87 (P = 0.0011);
MVP		0.84
MPC		0.92
ClinPred		0.99	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs121913548; hg19: chr12-69744004;