Genetic Variant LYST:c.11268-7_11268-5delTTT (chr1-235663082-TAAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000081.4(LYST):c.11268-7_11268-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,212,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000048 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LYST
NM_000081.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

6 publications found

Variant links:

Genes affected

LYST (HGNC:1968): (lysosomal trafficking regulator) This gene encodes a protein that regulates intracellular protein trafficking in endosomes, and may be involved in pigmentation. Mutations in this gene are associated with Chediak-Higashi syndrome, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants, though the full-length nature of some of these variants has not been determined. [provided by RefSeq, Apr 2013]

LYST Gene-Disease associations (from GenCC):

Chediak-Higashi syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp
attenuated Chédiak-Higashi syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LYST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.11268-7_11268-5delTTT		splice_region intron	N/A	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.11268-7_11268-5delTTT		splice_region intron	N/A	NP_001288294.1	Q99698-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LYST	ENST00000389793.7	TSL:5 MANE Select	c.11268-7_11268-5delTTT	splice_region intron	N/A	ENSP00000374443.2	Q99698-1
LYST	ENST00000697235.1		c.1818-7_1818-5delTTT	splice_region intron	N/A	ENSP00000513202.1	A0A8V8TL78
LYST	ENST00000462376.2	TSL:4	n.3087-7_3087-5delTTT	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149406

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000184

AC:

AN:

163066

AF XY:

0.0000114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000243

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000478

AC:

AN:

1212328

Hom.:

AF XY:

0.0000492

AC XY:

AN XY:

609902

show subpopulations

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

African (AFR)

AF:

0.0000773

AC:

AN:

25886

American (AMR)

AF:

0.0000251

AC:

AN:

39802

Ashkenazi Jewish (ASJ)

AF:

0.0000435

AC:

AN:

22970

East Asian (EAS)

AF:

0.0000298

AC:

AN:

33502

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4854

European-Non Finnish (NFE)

AF:

0.0000539

AC:

AN:

909232

Other (OTH)

AF:

0.0000585

AC:

AN:

51256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.235

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

149406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72722

African (AFR)

AF:

0.00

AC:

AN:

40930

American (AMR)

AF:

0.00

AC:

AN:

14884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

5070

South Asian (SAS)

AF:

0.00

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67196

Other (OTH)

AF:

0.00

AC:

AN:

2060

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

1-235663082-TAAAA-TA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over