NM_000239.3:c.253G>C

Variant names:

• chr12-69350224-G-C
• rs121913548
• NM_000239.3:c.253G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYZ NM_000239.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• Publications: 4 publications found

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000239.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYZ	NM_000239.3	MANE Select	c.253G>C	p.Asp85His	missense	Exon 2 of 4	NP_000230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYZ	ENST00000261267.7	TSL:1 MANE Select	c.253G>C	p.Asp85His	missense	Exon 2 of 4	ENSP00000261267.2
	LYZ	ENST00000549690.1	TSL:2	c.253G>C	p.Asp85His	missense	Exon 2 of 3	ENSP00000449898.1
	LYZ	ENST00000548839.1	TSL:2	c.253G>C	p.Asp85His	missense	Exon 2 of 2	ENSP00000449969.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.3
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.75		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
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs121913548; hg19: chr12-69744004;