12-69353397-C-T

Variant names:

• chr12-69353397-C-T
• rs710794
• NM_000239.3:c.*178C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000239.3(LYZ):​c.*178C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.87 in 670,562 control chromosomes in the GnomAD database, including 254,579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60568 hom., cov: 32)
  • Exomes 𝑓: 0.86 (194011 hom.)
• Consequence: LYZ NM_000239.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0560
• Publications: 11 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

ENSG00000257764 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-69353397-C-T is Benign according to our data. Variant chr12-69353397-C-T is described in ClinVar as Benign. ClinVar VariationId is 310335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYZ	NM_000239.3	c.*178C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000261267.7	NP_000230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYZ	ENST00000261267.7	c.*178C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_000239.3	ENSP00000261267.2
LYZ	ENST00000549690.1	c.*132C>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000449898.1
ENSG00000257764	ENST00000548900.1	n.*96G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135426 AN: 152122 Hom.: 60512 Cov.: 32

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.832

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.833

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.859

GnomAD4 exome AF: 0.864 AC: 447933 AN: 518324 Hom.: 194011 Cov.: 5 AF XY: 0.864 AC XY: 241315 AN XY: 279262

African (AFR) AF: 0.968 AC: 13766 AN: 14222

American (AMR) AF: 0.903 AC: 25992 AN: 28770

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 14897 AN: 17864

East Asian (EAS) AF: 0.926 AC: 29250 AN: 31578

South Asian (SAS) AF: 0.887 AC: 49677 AN: 56012

European-Finnish (FIN) AF: 0.830 AC: 28425 AN: 34260

Middle Eastern (MID) AF: 0.767 AC: 2027 AN: 2642

European-Non Finnish (NFE) AF: 0.851 AC: 258980 AN: 304146

Other (OTH) AF: 0.864 AC: 24919 AN: 28830

GnomAD4 genome AF: 0.890 AC: 135541 AN: 152238 Hom.: 60568 Cov.: 32 AF XY: 0.888 AC XY: 66096 AN XY: 74432

African (AFR) AF: 0.968 AC: 40235 AN: 41556

American (AMR) AF: 0.888 AC: 13576 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 2887 AN: 3470

East Asian (EAS) AF: 0.929 AC: 4821 AN: 5188

South Asian (SAS) AF: 0.894 AC: 4320 AN: 4832

European-Finnish (FIN) AF: 0.833 AC: 8804 AN: 10574

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 58048 AN: 68012

Other (OTH) AF: 0.859 AC: 1815 AN: 2112

Alfa AF: 0.866 Hom.: 184056

Bravo AF: 0.896

Asia WGS AF: 0.906 AC: 3151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial visceral amyloidosis, Ostertag type Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.71
PhyloP100		0.056
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs710794; hg19: chr12-69747177;