rs144597913

Variant names:

• chr1-235734531-G-A
• rs144597913
• NM_000081.4:c.8487C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000081.4(LYST):​c.8487C>T​(p.Ile2829Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,634 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.13
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-235734531-G-A is Benign according to our data. Variant chr1-235734531-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522322.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00124 (189/152210) while in subpopulation NFE AF = 0.00241 (164/67962). AF 95% confidence interval is 0.00211. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.8487C>T	p.Ile2829Ile	synonymous	Exon 32 of 53	NP_000072.2
	LYST	NM_001301365.1		c.8487C>T	p.Ile2829Ile	synonymous	Exon 32 of 53	NP_001288294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.8487C>T	p.Ile2829Ile	synonymous	Exon 32 of 53	ENSP00000374443.2
	LYST	ENST00000697241.1		c.2967C>T	p.Ile989Ile	synonymous	Exon 16 of 26	ENSP00000513206.1
	LYST	ENST00000475277.2	TSL:5	c.582C>T	p.Ile194Ile	synonymous	Exon 4 of 15	ENSP00000513164.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00138 AC: 347 AN: 251298 AF XY: 0.00141

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00170 AC: 2482 AN: 1461424 Hom.: 3 Cov.: 30 AF XY: 0.00169 AC XY: 1231 AN XY: 727030

African (AFR) AF: 0.000359 AC: 12 AN: 33460

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000928 AC: 80 AN: 86246

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00204 AC: 2271 AN: 1111658

Other (OTH) AF: 0.00113 AC: 68 AN: 60380

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74424

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00241 AC: 164 AN: 67962

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00114

EpiCase AF: 0.00224

EpiControl AF: 0.00219

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Chédiak-Higashi syndrome (3)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.7
DANN	Benign	0.72
PhyloP100		1.1
Mutation Taster		=99/1	polymorphism

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: rs144597913; hg19: chr1-235897831;