11-18291798-G-T

Variant names:

• chr11-18291798-G-T
• rs753514793
• NM_181507.2:c.2084C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_181507.2(HPS5):​c.2084C>A​(p.Ser695Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S695F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPS5 NM_181507.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.967
• Publications: 0 publications found

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This 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 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

HPS5 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 5

  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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity HPS5_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10844883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.2084C>A	p.Ser695Tyr	missense_variant	Exon 16 of 23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.2084C>A	p.Ser695Tyr	missense_variant	Exon 16 of 23	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.60
DEOGEN2	Benign	0.13	.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	.;M;.
PhyloP100		0.97
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.24	.;B;.
Vest4		0.32
MutPred		0.22		.;Gain of solvent accessibility (P = 0.0471);.;
MVP		0.69
MPC		0.12
ClinPred		0.13	T
GERP RS		2.6
Varity_R		0.025
gMVP		0.23
Mutation Taster		=94/6	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: rs753514793; hg19: chr11-18313345;