rs61738992

Variant names:

• chr1-235755570-T-G
• rs61738992
• NM_000081.4:c.7137A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-235755570-T-G
• chr1-235755570-T-A

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.7137A>C​(p.Leu2379Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,613,120 control chromosomes in the GnomAD database, including 1,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (98 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1140 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.458
• Publications: 7 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=-0.48).
• BP6: Variant 1-235755570-T-G is Benign according to our data. Variant chr1-235755570-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.458 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0632 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.7137A>C	p.Leu2379Leu	synonymous	Exon 25 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.7137A>C	p.Leu2379Leu	synonymous	Exon 25 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.7137A>C	p.Leu2379Leu	synonymous	Exon 25 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.1569A>C	p.Leu523Leu	synonymous	Exon 8 of 26	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000461526.2	TSL:3	n.1812A>C		non_coding_transcript_exon	Exon 9 of 28	ENSP00000513165.1	A0A8V8TL52

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4371 AN: 152150 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0345 AC: 8675 AN: 251358 AF XY: 0.0332

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.0798

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0337

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0362 AC: 52860 AN: 1460852 Hom.: 1140 Cov.: 31 AF XY: 0.0357 AC XY: 25972 AN XY: 726852

African (AFR) AF: 0.00499 AC: 167 AN: 33470

American (AMR) AF: 0.0775 AC: 3465 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 611 AN: 26122

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39678

South Asian (SAS) AF: 0.0277 AC: 2385 AN: 86232

European-Finnish (FIN) AF: 0.0337 AC: 1798 AN: 53410

Middle Eastern (MID) AF: 0.0166 AC: 96 AN: 5768

European-Non Finnish (NFE) AF: 0.0382 AC: 42466 AN: 1111090

Other (OTH) AF: 0.0309 AC: 1866 AN: 60364

GnomAD4 genome AF: 0.0287 AC: 4375 AN: 152268 Hom.: 98 Cov.: 32 AF XY: 0.0291 AC XY: 2167 AN XY: 74452

African (AFR) AF: 0.00647 AC: 269 AN: 41578

American (AMR) AF: 0.0665 AC: 1017 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4828

European-Finnish (FIN) AF: 0.0311 AC: 330 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0361 AC: 2454 AN: 68004

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0258 Hom.: 49

Bravo AF: 0.0309

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0319

EpiControl AF: 0.0311

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	2	Chédiak-Higashi syndrome (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.3
DANN	Benign	0.74
PhyloP100		0.46
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61738992; hg19: chr1-235918870; COSMIC: COSV67715043; COSMIC: COSV67715043;