chr12-69350234-C-A

Variant names:

• chr12-69350234-C-A
• rs1800973
• NM_000239.3:c.263C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000239.3(LYZ):​c.263C>A​(p.Thr88Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0532 in 1,613,898 control chromosomes in the GnomAD database, including 2,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (174 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2454 hom.)
• Consequence: LYZ NM_000239.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.85
• Publications: 37 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: Benign. The variant received -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0052376688).
• BP6: Variant 12-69350234-C-A is Benign according to our data. Variant chr12-69350234-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYZ	NM_000239.3	c.263C>A	p.Thr88Asn	missense_variant	Exon 2 of 4	ENST00000261267.7	NP_000230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYZ	ENST00000261267.7	c.263C>A	p.Thr88Asn	missense_variant	Exon 2 of 4	1	NM_000239.3	ENSP00000261267.2
LYZ	ENST00000549690.1	c.263C>A	p.Thr88Asn	missense_variant	Exon 2 of 3	2		ENSP00000449898.1
LYZ	ENST00000548839.1	c.263C>A	p.Thr88Asn	missense_variant	Exon 2 of 2	2		ENSP00000449969.1

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6398 AN: 152070 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.0381

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0680

Gnomad OTH AF: 0.0413

GnomAD2 exomes AF: 0.0422 AC: 10610 AN: 251424 AF XY: 0.0425

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0742

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0543 AC: 79435 AN: 1461710 Hom.: 2454 Cov.: 31 AF XY: 0.0538 AC XY: 39085 AN XY: 727158

African (AFR) AF: 0.00869 AC: 291 AN: 33480

American (AMR) AF: 0.0254 AC: 1135 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0719 AC: 1878 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39682

South Asian (SAS) AF: 0.00987 AC: 851 AN: 86256

European-Finnish (FIN) AF: 0.0441 AC: 2355 AN: 53418

Middle Eastern (MID) AF: 0.0199 AC: 115 AN: 5768

European-Non Finnish (NFE) AF: 0.0630 AC: 70081 AN: 1111862

Other (OTH) AF: 0.0451 AC: 2726 AN: 60390

GnomAD4 genome AF: 0.0421 AC: 6400 AN: 152188 Hom.: 174 Cov.: 32 AF XY: 0.0389 AC XY: 2893 AN XY: 74390

African (AFR) AF: 0.0108 AC: 449 AN: 41512

American (AMR) AF: 0.0307 AC: 469 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 254 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4822

European-Finnish (FIN) AF: 0.0381 AC: 404 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0680 AC: 4627 AN: 67998

Other (OTH) AF: 0.0408 AC: 86 AN: 2106

Alfa AF: 0.0572 Hom.: 1247

Bravo AF: 0.0406

TwinsUK AF: 0.0593 AC: 220

ALSPAC AF: 0.0675 AC: 260

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0698 AC: 600

ExAC AF: 0.0427 AC: 5186

Asia WGS AF: 0.00635 AC: 23 AN: 3478

EpiCase AF: 0.0643

EpiControl AF: 0.0644

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial visceral amyloidosis, Ostertag type Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Thr88Asn variant, sometimes called p.Thr70Asn due to a difference in cDNA numbering, in LYZ has been identified in cis with another missense variant in an individual with ALys amyloidosis (PMID: 16329101), but has also been identified in >6% of European (non-Finnish) chromosomes and 151 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for ALys amyloidosis. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;T;T
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.9	H;.;.
PhyloP100		2.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.057	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.46
MPC		0.87
ClinPred		0.042	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.73
Mutation Taster		=99/1	polymorphism (auto)

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: rs1800973; hg19: chr12-69744014; COSMIC: COSV54261430; COSMIC: COSV54261430;