22-37620842-G-A

Position:

• chr22-37620842-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013365.5(GGA1):​c.457G>A​(p.Asp153Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GGA1 NM_013365.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

Genes affected

GGA1 (HGNC:17842): (golgi associated, gamma adaptin ear containing, ARF binding protein 1) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) protein family. Members of this family are ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GGA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGA1	NM_013365.5	c.457G>A	p.Asp153Asn	missense_variant	6/17	ENST00000343632.9	NP_037497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGA1	ENST00000343632.9	c.457G>A	p.Asp153Asn	missense_variant	6/17	1	NM_013365.5	ENSP00000341344.4
GGA1	ENST00000381756.9	c.508G>A	p.Asp170Asn	missense_variant	6/17	1		ENSP00000371175.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.457G>A (p.D153N) alteration is located in exon 6 (coding exon 6) of the GGA1 gene. This alteration results from a G to A substitution at nucleotide position 457, causing the aspartic acid (D) at amino acid position 153 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T;.;.;.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T;D;.;T;T;T;.;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.082	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.;L;.;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.36	T;T;T;T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.;.;.
Vest4		0.25
MutPred		0.21		.;Gain of methylation at K167 (P = 0.0706);.;.;.;.;.;.;
MVP		0.29
MPC		0.41
ClinPred		0.25	T
GERP RS		4.5
Varity_R		0.069
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.43		Position offset: 39

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: chr22-38016849;