3-149145364-A-G

Variant names:

• chr3-149145364-A-G
• rs11718908
• NM_032383.5:c.981A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032383.5(HPS3):​c.981A>G​(p.Thr327Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,610,020 control chromosomes in the GnomAD database, including 43,355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T327T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6353 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37002 hom.)
• Consequence: HPS3 NM_032383.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.177
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-149145364-A-G is Benign according to our data. Variant chr3-149145364-A-G is described in ClinVar as Benign. ClinVar VariationId is 178777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.177 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 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.981A>G	p.Thr327Thr	synonymous	Exon 5 of 17	NP_115759.2
	HPS3	NM_001308258.2		c.486A>G	p.Thr162Thr	synonymous	Exon 4 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.981A>G	p.Thr327Thr	synonymous	Exon 5 of 17	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.981A>G	p.Thr327Thr	synonymous	Exon 5 of 17	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.981A>G	p.Thr327Thr	synonymous	Exon 5 of 17	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41606 AN: 151900 Hom.: 6331 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.239 AC: 60093 AN: 251098 AF XY: 0.233

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.276

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.220 AC: 321145 AN: 1458002 Hom.: 37002 Cov.: 32 AF XY: 0.220 AC XY: 159676 AN XY: 725512

African (AFR) AF: 0.433 AC: 14450 AN: 33368

American (AMR) AF: 0.290 AC: 12975 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 5256 AN: 26106

East Asian (EAS) AF: 0.147 AC: 5832 AN: 39670

South Asian (SAS) AF: 0.240 AC: 20637 AN: 86120

European-Finnish (FIN) AF: 0.271 AC: 14411 AN: 53260

Middle Eastern (MID) AF: 0.204 AC: 1176 AN: 5762

European-Non Finnish (NFE) AF: 0.210 AC: 232558 AN: 1108740

Other (OTH) AF: 0.230 AC: 13850 AN: 60264

GnomAD4 genome AF: 0.274 AC: 41677 AN: 152018 Hom.: 6353 Cov.: 32 AF XY: 0.276 AC XY: 20510 AN XY: 74330

African (AFR) AF: 0.425 AC: 17598 AN: 41430

American (AMR) AF: 0.252 AC: 3846 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 703 AN: 3468

East Asian (EAS) AF: 0.157 AC: 813 AN: 5174

South Asian (SAS) AF: 0.237 AC: 1144 AN: 4822

European-Finnish (FIN) AF: 0.274 AC: 2896 AN: 10576

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14017 AN: 67968

Other (OTH) AF: 0.247 AC: 521 AN: 2108

Alfa AF: 0.228 Hom.: 6996

Bravo AF: 0.280

Asia WGS AF: 0.243 AC: 846 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.202

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.54
PhyloP100		-0.18
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: rs11718908; hg19: chr3-148863151; COSMIC: COSV56054680;