Genetic Variant NM_000512.5:c.47T>A (chr16-88856831-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V16L) has been classified 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.04

Publications

3 publications found

Variant links:

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]

GALNS links:

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]

TRAPPC2L Gene-Disease associations (from GenCC):

encephalopathy, progressive, early-onset, with episodic rhabdomyolysis
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

TRAPPC2L links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000512.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNS	NM_000512.5	MANE Select	c.47T>A	p.Val16Glu	missense	Exon 1 of 14	NP_000503.1
GALNS	NM_001323544.2		c.-106T>A		5_prime_UTR	Exon 1 of 15	NP_001310473.1
GALNS	NM_001323543.2		c.-385T>A		5_prime_UTR	Exon 1 of 13	NP_001310472.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNS	ENST00000268695.10	TSL:1 MANE Select	c.47T>A	p.Val16Glu	missense	Exon 1 of 14	ENSP00000268695.5
GALNS	ENST00000568311.1	TSL:1	c.47T>A	p.Val16Glu	missense	Exon 1 of 3	ENSP00000455006.1
TRAPPC2L	ENST00000564365.5	TSL:1	c.-398+585A>T		intron	N/A	ENSP00000455447.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1372550

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678174

African (AFR)

AF:

0.00

AC:

AN:

28668

American (AMR)

AF:

0.00

AC:

AN:

35556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24340

East Asian (EAS)

AF:

0.00

AC:

AN:

33108

South Asian (SAS)

AF:

0.00

AC:

AN:

77786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077486

Other (OTH)

AF:

0.00

AC:

AN:

57258

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis, MPS-IV-A (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.36

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

0.0

PhyloP100

2.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

Sift4G

Benign

0.098

Polyphen

0.72

Vest4

0.47

MutPred

0.69

Gain of disorder (P = 0.029)

MVP

0.87

MPC

0.18

ClinPred

0.35

GERP RS

2.8

PromoterAI

-0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.40

gMVP

0.68

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over