22-26443118-GG-TC

Variant names:

• chr22-26443118-GG-TC
• NM_020437.5:c.1022_1023delGGinsTC
• ASPHD2 p.Arg341Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_020437.5(ASPHD2):​c.1022_1023delGGinsTC​(p.Arg341Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. R341W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ASPHD2 NM_020437.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.98
• Publications: 0 publications found

Genes affected

ASPHD2 (HGNC:30437): (aspartate beta-hydroxylase domain containing 2) Predicted to enable dioxygenase activity and metal ion binding activity. Predicted to be involved in peptidyl-amino acid modification. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ASPH2_HUMAN
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020437.5. 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
	ASPHD2	NM_020437.5	MANE Select	c.1022_1023delGGinsTC	p.Arg341Leu	missense	N/A	NP_065170.2	Q6ICH7
	HPS4	NM_001349904.2		c.*1563_*1564delCCinsGA		3_prime_UTR	Exon 14 of 14	NP_001336833.1
	HPS4	NM_001349905.1		c.*1563_*1564delCCinsGA		3_prime_UTR	Exon 14 of 14	NP_001336834.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPHD2	ENST00000215906.6	TSL:1 MANE Select	c.1022_1023delGGinsTC	p.Arg341Leu	missense	N/A	ENSP00000215906.5	Q6ICH7
	ASPHD2	ENST00000851348.1		c.1022_1023delGGinsTC	p.Arg341Leu	missense	N/A	ENSP00000521407.1
	ASPHD2	ENST00000851349.1		c.1022_1023delGGinsTC	p.Arg341Leu	missense	N/A	ENSP00000521408.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-26839084;