chr12-69350215-T-C

Variant names:

• chr12-69350215-T-C
• rs387906536
• NM_000239.3:c.244T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Moderate

The NM_000239.3(LYZ):​c.244T>C​(p.Trp82Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LYZ NM_000239.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.53
• Publications: 12 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: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000239.3 (LYZ) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_000239.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 12-69350215-T-C is Pathogenic according to our data. Variant chr12-69350215-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14376.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYZ	NM_000239.3	c.244T>C	p.Trp82Arg	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.244T>C	p.Trp82Arg	missense_variant	Exon 2 of 4	1	NM_000239.3	ENSP00000261267.2
LYZ	ENST00000549690.1	c.244T>C	p.Trp82Arg	missense_variant	Exon 2 of 3	2		ENSP00000449898.1
LYZ	ENST00000548839.1	c.244T>C	p.Trp82Arg	missense_variant	Exon 2 of 2	2		ENSP00000449969.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 23, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial visceral amyloidosis, Ostertag type Pathogenic:1

Mar 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.3	H;.;.
PhyloP100		6.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-14	D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.84		Gain of catalytic residue at W82 (P = 0.003);Gain of catalytic residue at W82 (P = 0.003);Gain of catalytic residue at W82 (P = 0.003);
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs387906536; hg19: chr12-69743995;