17-75239838-C-T

Variant names:

• chr17-75239838-C-T
• rs141316552
• NM_138619.4:c.1534G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_138619.4(GGA3):​c.1534G>A​(p.Ala512Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,613,954 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (9 hom.)
• Consequence: GGA3 NM_138619.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.842

Genes affected

GGA3 (HGNC:17079): (golgi associated, gamma adaptin ear containing, ARF binding protein 3) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes 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 have been identified in this gene. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002592057).
• BP6: Variant 17-75239838-C-T is Benign according to our data. Variant chr17-75239838-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2229758.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGA3	NM_138619.4	c.1534G>A	p.Ala512Thr	missense_variant	Exon 13 of 17	ENST00000537686.6	NP_619525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGA3	ENST00000537686.6	c.1534G>A	p.Ala512Thr	missense_variant	Exon 13 of 17	1	NM_138619.4	ENSP00000438085.3

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000815 AC: 204 AN: 250242 Hom.: 2 AF XY: 0.000819 AC XY: 111 AN XY: 135452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000486 AC: 711 AN: 1461626 Hom.: 9 Cov.: 32 AF XY: 0.000521 AC XY: 379 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000990 Hom.: 3

Bravo AF: 0.000570

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000577 AC: 70

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 04, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.12
DANN	Benign	0.46
DEOGEN2	Benign	0.021	.;T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.16	T;.;T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0026	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.57	.;N;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N;.;.;.;.
REVEL	Benign	0.0080
Sift	Benign	0.042	D;.;.;.;.
Sift4G	Benign	0.72	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.062
MVP		0.25
ClinPred		0.014	T
GERP RS		-9.0
Varity_R		0.071
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs141316552; hg19: chr17-73235919;