rs1800973

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.85

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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	Protein	UniProt
LYZ	NM_000239.3 linkuse as main transcript	c.263C>A	p.Thr88Asn	missense_variant	2/4	ENST00000261267.7	NP_000230.1	P61626B2R4C5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LYZ	ENST00000261267.7 linkuse as main transcript	c.263C>A	p.Thr88Asn	missense_variant	2/4	1	NM_000239.3	ENSP00000261267.2	P61626
LYZ	ENST00000549690.1 linkuse as main transcript	c.263C>A	p.Thr88Asn	missense_variant	2/3	2		ENSP00000449898.1	A0A0B4J259
LYZ	ENST00000548839.1 linkuse as main transcript	c.263C>A	p.Thr88Asn	missense_variant	2/2	2		ENSP00000449969.1	F8VV32

Frequencies

GnomAD3 genomes

AF:

0.0421

AC:

6398

AN:

152070

Hom.:

174

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0538

AC XY:

39085

AN XY:

727158

show subpopulations

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.:

AF XY:

0.0389

AC XY:

2893

AN XY:

74390

show subpopulations

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:

ESP6500EA

AF:

0.0698

AC:

600

ExAC

AF:

0.0427

AC:

5186

Asia WGS

AF:

0.00635

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Familial visceral amyloidosis, Ostertag type

Benign:2

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. -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

T;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;T;T

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.9

H;.;.

PrimateAI

Benign

0.41

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over