rs757222354

Variant names:

• chr1-235775041-G-A
• rs757222354
• NM_000081.4:c.5506C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-235775041-G-A
• chr1-235775041-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Moderate PP5_Moderate

The NM_000081.4(LYST):​c.5506C>T​(p.Arg1836*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,418 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 (★). Synonymous variant affecting the same amino acid position (i.e. R1836R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LYST NM_000081.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 2.00
• Publications: 9 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-235775041-G-A is Pathogenic according to our data. Variant chr1-235775041-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 180625.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.5506C>T	p.Arg1836*	stop_gained	Exon 18 of 53	NP_000072.2
	LYST	NM_001301365.1		c.5506C>T	p.Arg1836*	stop_gained	Exon 18 of 53	NP_001288294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.5506C>T	p.Arg1836*	stop_gained	Exon 18 of 53	ENSP00000374443.2
	LYST	ENST00000489585.5	TSL:1	n.5506C>T		non_coding_transcript_exon	Exon 18 of 23	ENSP00000513166.1
	LYST	ENST00000461526.2	TSL:3	n.181C>T		non_coding_transcript_exon	Exon 2 of 28	ENSP00000513165.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250078 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459418 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726142

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111084

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Chédiak-Higashi syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.0098
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		2.0
Vest4		0.89
GERP RS		-1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.96		Position offset: 2

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

Other links and lift over

dbSNP: rs757222354; hg19: chr1-235938341; COSMIC: COSV106113540;