10-102065528-C-A

Variant names:

• chr10-102065528-C-A
• rs1320012863
• NM_024747.6:c.54C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_024747.6(HPS6):​c.54C>A​(p.Gly18Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G18G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HPS6 NM_024747.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 0 publications found

Genes affected

HPS6 (HGNC:18817): (HPS6 biogenesis of lysosomal organelles complex 2 subunit 3) This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 5 protein. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 6. [provided by RefSeq, Jul 2008]

HPS6 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 6

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.12).
• BP7: Synonymous conserved (PhyloP=0.289 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024747.6. 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
	HPS6	NM_024747.6	MANE Select	c.54C>A	p.Gly18Gly	synonymous	Exon 1 of 1	NP_079023.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS6	ENST00000299238.7	TSL:6 MANE Select	c.54C>A	p.Gly18Gly	synonymous	Exon 1 of 1	ENSP00000299238.5	Q86YV9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398772 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693658

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29438

American (AMR) AF: 0.00 AC: 0 AN: 39368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24766

East Asian (EAS) AF: 0.00 AC: 0 AN: 35352

South Asian (SAS) AF: 0.00 AC: 0 AN: 80024

European-Finnish (FIN) AF: 0.0000284 AC: 1 AN: 35186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4244

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092244

Other (OTH) AF: 0.00 AC: 0 AN: 58150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		0.29
PromoterAI		0.014	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1320012863; hg19: chr10-103825285;