22-26451980-C-T

Variant names:

• chr22-26451980-C-T
• rs534586940
• NM_022081.6:c.*1253G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_022081.6(HPS4):​c.*1253G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 175,478 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 0.0015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.525
• Publications: 0 publications found

Genes affected

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HPS4 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-26451980-C-T is Benign according to our data. Variant chr22-26451980-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 340971.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00154 (210/136450) while in subpopulation AFR AF = 0.00494 (187/37834). AF 95% confidence interval is 0.00436. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. 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
	HPS4	NM_022081.6	MANE Select	c.*1253G>A		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1253G>A		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1253G>A		3_prime_UTR	Exon 15 of 15	NP_001336830.1	F1LLU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	ENST00000398145.7	TSL:1 MANE Select	c.*1253G>A		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000422379.3	TSL:5	c.*1253G>A		3_prime_UTR	Exon 15 of 15	ENSP00000415081.3	F1LLU8
	HPS4	ENST00000473782.2	TSL:2	c.*1253G>A		3_prime_UTR	Exon 15 of 15	ENSP00000514223.1	Q9NQG7-1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 210 AN: 136342 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000845

Gnomad ASJ AF: 0.000301

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.000127

Gnomad OTH AF: 0.000563

GnomAD4 exome AF: 0.000179 AC: 7 AN: 39028 Hom.: 0 Cov.: 0 AF XY: 0.000133 AC XY: 3 AN XY: 22516

African (AFR) AF: 0.00327 AC: 2 AN: 612

American (AMR) AF: 0.000534 AC: 1 AN: 1874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 934

East Asian (EAS) AF: 0.00 AC: 0 AN: 974

South Asian (SAS) AF: 0.00 AC: 0 AN: 6800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 112

European-Non Finnish (NFE) AF: 0.0000806 AC: 2 AN: 24800

Other (OTH) AF: 0.00123 AC: 2 AN: 1626

GnomAD4 genome AF: 0.00154 AC: 210 AN: 136450 Hom.: 0 Cov.: 30 AF XY: 0.00130 AC XY: 85 AN XY: 65400

African (AFR) AF: 0.00494 AC: 187 AN: 37834

American (AMR) AF: 0.000844 AC: 11 AN: 13034

Ashkenazi Jewish (ASJ) AF: 0.000301 AC: 1 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4524

South Asian (SAS) AF: 0.00 AC: 0 AN: 3882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7922

Middle Eastern (MID) AF: 0.00725 AC: 2 AN: 276

European-Non Finnish (NFE) AF: 0.000127 AC: 8 AN: 63030

Other (OTH) AF: 0.000556 AC: 1 AN: 1798

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00161

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hermansky-Pudlak syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.83
PhyloP100		0.53
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: rs534586940; hg19: chr22-26847946;