NM_000081.4:c.7857T>C

Variant names:

• chr1-235746451-A-G
• rs34160788
• NM_000081.4:c.7857T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000081.4(LYST):​c.7857T>C​(p.His2619His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,613,916 control chromosomes in the GnomAD database, including 339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (169 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.711
• 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-235746451-A-G is Benign according to our data. Variant chr1-235746451-A-G is described in ClinVar as Benign. ClinVar VariationId is 254940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.711 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

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.7857T>C	p.His2619His	synonymous	Exon 29 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.7857T>C	p.His2619His	synonymous	Exon 29 of 53	NP_001288294.1	Q99698-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.7857T>C	p.His2619His	synonymous	Exon 29 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.2337T>C	p.His779His	synonymous	Exon 13 of 26	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000461526.2	TSL:3	n.2532T>C		non_coding_transcript_exon	Exon 13 of 28	ENSP00000513165.1	A0A8V8TL52

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4135 AN: 152138 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00744 AC: 1869 AN: 251332 AF XY: 0.00544

Gnomad AFR exome AF: 0.0992

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00287 AC: 4199 AN: 1461660 Hom.: 169 Cov.: 31 AF XY: 0.00249 AC XY: 1813 AN XY: 727126

African (AFR) AF: 0.0939 AC: 3142 AN: 33462

American (AMR) AF: 0.00582 AC: 260 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53412

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.000281 AC: 312 AN: 1111878

Other (OTH) AF: 0.00699 AC: 422 AN: 60384

GnomAD4 genome AF: 0.0273 AC: 4153 AN: 152256 Hom.: 170 Cov.: 32 AF XY: 0.0259 AC XY: 1925 AN XY: 74454

African (AFR) AF: 0.0943 AC: 3916 AN: 41530

American (AMR) AF: 0.0108 AC: 165 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68030

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0115 Hom.: 56

Bravo AF: 0.0320

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.50
DANN	Benign	0.48
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34160788; hg19: chr1-235909751;