chr3-149129654-T-C

Variant names:

• chr3-149129654-T-C
• rs13089410
• NM_032383.5:c.-70T>C

Variant summary

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

The NM_032383.5(HPS3):​c.-70T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,225,622 control chromosomes in the GnomAD database, including 783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (65 hom., cov: 33)
  • Exomes 𝑓: 0.033 (718 hom.)
• Consequence: HPS3 NM_032383.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.76
• Publications: 5 publications found

Genes affected

HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

HPS3 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  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=-0.8).
• BP6: Variant 3-149129654-T-C is Benign according to our data. Variant chr3-149129654-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 343688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032383.5. 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
	HPS3	NM_032383.5	MANE Select	c.-70T>C		5_prime_UTR	Exon 1 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.-70T>C		5_prime_UTR	Exon 1 of 16	NP_001295187.1	G5E9V4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.-70T>C		5_prime_UTR	Exon 1 of 17	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000960205.1		c.-70T>C		5_prime_UTR	Exon 1 of 17	ENSP00000630264.1
	HPS3	ENST00000870869.1		c.-70T>C		5_prime_UTR	Exon 1 of 16	ENSP00000540928.1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3561 AN: 152086 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0661

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0327 AC: 35075 AN: 1073418 Hom.: 718 Cov.: 14 AF XY: 0.0340 AC XY: 17949 AN XY: 528536

African (AFR) AF: 0.00531 AC: 117 AN: 22028

American (AMR) AF: 0.0169 AC: 347 AN: 20522

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 749 AN: 17206

East Asian (EAS) AF: 0.0000631 AC: 2 AN: 31692

South Asian (SAS) AF: 0.0698 AC: 4134 AN: 59256

European-Finnish (FIN) AF: 0.0248 AC: 764 AN: 30810

Middle Eastern (MID) AF: 0.0416 AC: 135 AN: 3242

European-Non Finnish (NFE) AF: 0.0324 AC: 27299 AN: 842282

Other (OTH) AF: 0.0329 AC: 1528 AN: 46380

GnomAD4 genome AF: 0.0234 AC: 3562 AN: 152204 Hom.: 65 Cov.: 33 AF XY: 0.0235 AC XY: 1746 AN XY: 74420

African (AFR) AF: 0.00561 AC: 233 AN: 41554

American (AMR) AF: 0.0198 AC: 303 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.0666 AC: 321 AN: 4820

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2293 AN: 67978

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0291 Hom.: 41

Bravo AF: 0.0216

Asia WGS AF: 0.0210 AC: 75 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hermansky-Pudlak syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.62
PhyloP100		-1.8
PromoterAI		0.26	Neutral
Mutation Taster		=300/0	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: rs13089410; hg19: chr3-148847441;