Genetic Variant NM_000081.4: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: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4 link	c.11268-7_11268-5delTTT		splice_region_variant, intron_variant	Intron 52 of 52	ENST00000389793.7	NP_000072.2	Q99698-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7 link	c.11268-7_11268-5delTTT		splice_region_variant, intron_variant	Intron 52 of 52	5	NM_000081.4	ENSP00000374443.2		Q99698-1

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 = 0.000000), 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 v4.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over