16-71734650-C-T

Position:

• chr16-71734650-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000299980.9(AP1G1):​c.2326G>A​(p.Gly776Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP1G1 ENST00000299980.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP1G1	NM_001128.6	c.2326G>A	p.Gly776Arg	missense_variant	22/23	ENST00000299980.9	NP_001119.3
AP1G1	NM_001030007.2	c.2335G>A	p.Gly779Arg	missense_variant	23/24		NP_001025178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1G1	ENST00000299980.9	c.2326G>A	p.Gly776Arg	missense_variant	22/23	1	NM_001128.6	ENSP00000299980	P4
AP1G1	ENST00000564155.5	c.601G>A	p.Gly201Arg	missense_variant	6/7	1		ENSP00000454219
AP1G1	ENST00000393512.7	c.2335G>A	p.Gly779Arg	missense_variant	23/24	5		ENSP00000377148	A1
AP1G1	ENST00000569748.5	c.2326G>A	p.Gly776Arg	missense_variant	25/26	2		ENSP00000454523	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;T;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.6	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.033	D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.96
MVP		0.84
MPC		2.3
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.65

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-71768553;