1-235775088-TAA-T

Variant names:

• chr1-235775088-TAA-T
• rs557545474
• NM_000081.4:c.5461-4_5461-3delTT

Variant summary

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

The NM_000081.4(LYST):​c.5461-4_5461-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 1,262,848 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 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 2 publications found

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

ACMG classification

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	c.5461-4_5461-3delTT		splice_region_variant, intron_variant	Intron 17 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.5461-4_5461-3delTT		splice_region_variant, intron_variant	Intron 17 of 52	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146224 Hom.: 0 Cov.: 32

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000413 AC: 4 AN: 96916 AF XY: 0.0000391

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000426

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 29 AN: 1116624 Hom.: 0 AF XY: 0.0000234 AC XY: 13 AN XY: 556622

⚠️ 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: 25392

American (AMR) AF: 0.00 AC: 0 AN: 33968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19256

East Asian (EAS) AF: 0.00 AC: 0 AN: 29306

South Asian (SAS) AF: 0.0000300 AC: 2 AN: 66712

European-Finnish (FIN) AF: 0.0000261 AC: 1 AN: 38260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4552

European-Non Finnish (NFE) AF: 0.0000281 AC: 24 AN: 853524

Other (OTH) AF: 0.0000438 AC: 2 AN: 45654

⚠️ 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.

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146224 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 71104

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

African (AFR) AF: 0.00 AC: 0 AN: 40142

American (AMR) AF: 0.00 AC: 0 AN: 14676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66034

Other (OTH) AF: 0.00 AC: 0 AN: 1986

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs557545474; hg19: chr1-235938388; COSMIC: COSV67712314;