chr16-71739301-CT-C

Position:

• chr16-71739301-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000299980.9(AP1G1):​c.2039del​(p.Gln680ArgfsTer36) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AP1G1 ENST00000299980.9 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.93

Genes affected

AP1G1 (HGNC:555): (adaptor related protein complex 1 subunit gamma 1) Adaptins are important components of clathrin-coated vesicles transporting ligand-receptor complexes from the plasma membrane or from the trans-Golgi network to lysosomes. The adaptin family of proteins is composed of four classes of molecules named alpha, beta-, beta prime- and gamma- adaptins. Adaptins, together with medium and small subunits, form a heterotetrameric complex called an adaptor, whose role is to promote the formation of clathrin-coated pits and vesicles. The protein encoded by this gene is a gamma-adaptin protein and it belongs to the adaptor complexes large subunits family. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-71739301-CT-C is Pathogenic according to our data. Variant chr16-71739301-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3062338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP1G1	NM_001128.6	c.2039del	p.Gln680ArgfsTer36	frameshift_variant	20/23	ENST00000299980.9	NP_001119.3
AP1G1	NM_001030007.2	c.2048del	p.Gln683ArgfsTer36	frameshift_variant	21/24		NP_001025178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1G1	ENST00000299980.9	c.2039del	p.Gln680ArgfsTer36	frameshift_variant	20/23	1	NM_001128.6	ENSP00000299980	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Usmani-Riazuddin syndrome, autosomal dominant Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Feb 27, 2024

The detected change is not reported in the general population (gnomAD) (as of February 27, 2024). It has not yet been described in the ClinVar database or in the literature. The variant represents a frame shift with a subsequent stop codon. This usually leads to either premature termination of translation or a so-called “nonsense-mediated mRNA decay”. In both cases there is a loss of function of the protein. Intolerance to haploinsufficiency has been described as the pathomechanism for the gene under investigation. It is therefore very likely that it has a pathogenetic relevance. The variant is currently considered a “likely pathogenic variant” (ACMG criteria). -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-71773204;