16-88856831-A-T

Variant names:

• chr16-88856831-A-T
• rs794729202
• NM_000512.5:c.47T>A

Variant summary

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

The NM_000512.5(GALNS):​c.47T>A​(p.Val16Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.04

Genes affected

GALNS (HGNC:4122): (galactosamine (N-acetyl)-6-sulfatase) This gene encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. Sequence alterations including point, missense and nonsense mutations, as well as those that affect splicing, result in a deficiency of this enzyme. Deficiencies of this enzyme lead to Morquio A syndrome, a lysosomal storage disorder. [provided by RefSeq, Jul 2008]

TRAPPC2L (HGNC:30887): (trafficking protein particle complex subunit 2L) This gene encodes a protein that interacts with the tethering factor trafficking protein particle (TRAPP complex). TRAPP complexes mediate the contact between vescicles and target membranes, and thus, are involved in vescicle-mediated transport of proteins and lipids. The encoded protein is related to the X-linked trafficking protein particle complex 2. A related pseudogene is located on the X chromosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

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, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.47T>A	p.Val16Glu	missense_variant	Exon 1 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.47T>A	p.Val16Glu	missense_variant	Exon 1 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1372550 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 678174

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:1 Uncertain:1

Feb 01, 2021

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) -

Feb 26, 2013

Mendelics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.36	T;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.098	T;D;D
Polyphen		0.72	P;.;.
Vest4		0.47
MutPred		0.69		Gain of disorder (P = 0.029);Gain of disorder (P = 0.029);Gain of disorder (P = 0.029);
MVP		0.87
MPC		0.18
ClinPred		0.35	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.40
gMVP		0.68

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: rs794729202; hg19: chr16-88923239;