22-37620289-C-T

Variant names:

• chr22-37620289-C-T
• rs11543985
• NM_013365.5:c.355C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013365.5(GGA1):​c.355C>T​(p.Leu119Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. L119V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GGA1 NM_013365.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013365.5. 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
	GGA1	NM_013365.5	MANE Select	c.355C>T	p.Leu119Phe	missense	Exon 5 of 17	NP_037497.1	Q9UJY5-1
	GGA1	NM_001363771.2		c.406C>T	p.Leu136Phe	missense	Exon 5 of 17	NP_001350700.1	Q9UJY5-6
	GGA1	NM_001172687.2		c.355C>T	p.Leu119Phe	missense	Exon 5 of 17	NP_001166158.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGA1	ENST00000343632.9	TSL:1 MANE Select	c.355C>T	p.Leu119Phe	missense	Exon 5 of 17	ENSP00000341344.4	Q9UJY5-1
	GGA1	ENST00000381756.9	TSL:1	c.406C>T	p.Leu136Phe	missense	Exon 5 of 17	ENSP00000371175.5	Q9UJY5-6
	GGA1	ENST00000325180.12	TSL:1	c.355C>T	p.Leu119Phe	missense	Exon 5 of 15	ENSP00000321288.8	Q9UJY5-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.061	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.73		Gain of methylation at K131 (P = 0.1271)
MVP		0.50
MPC		0.95
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.51
gMVP		0.52
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11543985; hg19: chr22-38016296; COSMIC: COSV57331557; COSMIC: COSV57331557;