16-71739333-C-T

Position:

• chr16-71739333-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000299980.9(AP1G1):​c.2008G>A​(p.Ala670Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AP1G1 ENST00000299980.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.139

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057959616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP1G1	NM_001128.6	c.2008G>A	p.Ala670Thr	missense_variant	20/23	ENST00000299980.9	NP_001119.3
AP1G1	NM_001030007.2	c.2017G>A	p.Ala673Thr	missense_variant	21/24		NP_001025178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1G1	ENST00000299980.9	c.2008G>A	p.Ala670Thr	missense_variant	20/23	1	NM_001128.6	ENSP00000299980	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446316 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jun 07, 2024

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.038	T;T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.75	.;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.;N;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.52	N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.11
MVP		0.35
MPC		0.057
ClinPred		0.099	T
GERP RS		1.2
Varity_R		0.032
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs1381499563; hg19: chr16-71773236;