NM_000081.4:c.5922+10A>G

Variant names:

• chr1-235770150-T-C
• rs375422713
• NM_000081.4:c.5922+10A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000081.4(LYST):​c.5922+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,612,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: LYST NM_000081.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.43
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-235770150-T-C is Benign according to our data. Variant chr1-235770150-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 525194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000309 (47/152066) while in subpopulation NFE AF = 0.000544 (37/67984). AF 95% confidence interval is 0.000405. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.5922+10A>G		intron	N/A	NP_000072.2
	LYST	NM_001301365.1		c.5922+10A>G		intron	N/A	NP_001288294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.5922+10A>G		intron	N/A	ENSP00000374443.2
	LYST	ENST00000489585.5	TSL:1	n.5922+10A>G		intron	N/A	ENSP00000513166.1
	LYST	ENST00000697241.1		c.354+10A>G		intron	N/A	ENSP00000513206.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000319 AC: 80 AN: 251060 AF XY: 0.000324

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000593 AC: 866 AN: 1460404 Hom.: 0 Cov.: 31 AF XY: 0.000596 AC XY: 433 AN XY: 726506

African (AFR) AF: 0.0000898 AC: 3 AN: 33424

American (AMR) AF: 0.000246 AC: 11 AN: 44692

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5118

European-Non Finnish (NFE) AF: 0.000731 AC: 813 AN: 1111518

Other (OTH) AF: 0.000647 AC: 39 AN: 60276

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74280

African (AFR) AF: 0.0000965 AC: 4 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 67984

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000332

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.0
DANN	Benign	0.57
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs375422713; hg19: chr1-235933450;