NM_000081.4:c.6881+44A>G

Variant names:

• chr1-235758928-T-C
• rs3738519
• NM_000081.4:c.6881+44A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000081.4(LYST):​c.6881+44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,590,076 control chromosomes in the GnomAD database, including 56,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7337 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49419 hom.)
• Consequence: LYST NM_000081.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.83
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-235758928-T-C is Benign according to our data. Variant chr1-235758928-T-C is described in ClinVar as Benign. ClinVar VariationId is 254935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.6881+44A>G		intron_variant	Intron 23 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.6881+44A>G		intron_variant	Intron 23 of 52	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45117 AN: 151964 Hom.: 7328 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.241 AC: 59938 AN: 248736 AF XY: 0.236

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.00940

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.255 AC: 366148 AN: 1437994 Hom.: 49419 Cov.: 28 AF XY: 0.251 AC XY: 179980 AN XY: 716610

African (AFR) AF: 0.421 AC: 13881 AN: 32942

American (AMR) AF: 0.195 AC: 8718 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5945 AN: 25974

East Asian (EAS) AF: 0.0364 AC: 1435 AN: 39436

South Asian (SAS) AF: 0.169 AC: 14472 AN: 85418

European-Finnish (FIN) AF: 0.334 AC: 17815 AN: 53272

Middle Eastern (MID) AF: 0.177 AC: 1010 AN: 5718

European-Non Finnish (NFE) AF: 0.264 AC: 288354 AN: 1091010

Other (OTH) AF: 0.244 AC: 14518 AN: 59586

GnomAD4 genome AF: 0.297 AC: 45177 AN: 152082 Hom.: 7337 Cov.: 32 AF XY: 0.294 AC XY: 21876 AN XY: 74330

African (AFR) AF: 0.417 AC: 17292 AN: 41484

American (AMR) AF: 0.224 AC: 3422 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3468

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5178

South Asian (SAS) AF: 0.163 AC: 784 AN: 4814

European-Finnish (FIN) AF: 0.333 AC: 3515 AN: 10556

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18412 AN: 67984

Other (OTH) AF: 0.269 AC: 568 AN: 2110

Alfa AF: 0.274 Hom.: 2713

Bravo AF: 0.292

Asia WGS AF: 0.114 AC: 399 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.024
DANN	Benign	0.47
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs3738519; hg19: chr1-235922228;