12-69350234-C-A

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 2.85

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 Benign. Variant got -18 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
• 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 [Likely_benign]. Clinvar id is 310331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-69350234-C-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
LYZ	NM_000239.3	c.263C>A	p.Thr88Asn	missense_variant	2/4	ENST00000261267.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYZ	ENST00000261267.7	c.263C>A	p.Thr88Asn	missense_variant	2/4	1	NM_000239.3	P1
LYZ	ENST00000549690.1	c.263C>A	p.Thr88Asn	missense_variant	2/3	2
LYZ	ENST00000548839.1	c.263C>A	p.Thr88Asn	missense_variant	2/2	2

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

GnomAD3 exomes AF: 0.0422 AC: 10610 AN: 251424 Hom.: 297 AF XY: 0.0425 AC XY: 5774 AN XY: 135886

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 SAS exome AF: 0.00973

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

Gnomad4 AFR exome AF: 0.00869

Gnomad4 AMR exome AF: 0.0254

Gnomad4 ASJ exome AF: 0.0719

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00987

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.0630

Gnomad4 OTH exome AF: 0.0451

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

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0307

Gnomad4 ASJ AF: 0.0732

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0381

Gnomad4 NFE AF: 0.0680

Gnomad4 OTH AF: 0.0408

Alfa AF: 0.0595 Hom.: 675

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial visceral amyloidosis, Ostertag type Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

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;.;.
MutationTaster	Benign	1.0	D;D;D
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

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