NM_000512.5:c.47T>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000512.5(GALNS):​c.47T>C​(p.Val16Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,372,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V16L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38639286).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.47T>C	p.Val16Ala	missense	Exon 1 of 14	NP_000503.1
	GALNS	NM_001323544.2		c.-106T>C		5_prime_UTR	Exon 1 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.-385T>C		5_prime_UTR	Exon 1 of 13	NP_001310472.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.47T>C	p.Val16Ala	missense	Exon 1 of 14	ENSP00000268695.5
	GALNS	ENST00000568311.1	TSL:1	c.47T>C	p.Val16Ala	missense	Exon 1 of 3	ENSP00000455006.1
	TRAPPC2L	ENST00000564365.5	TSL:1	c.-398+585A>G		intron	N/A	ENSP00000455447.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1372550 Hom.: 0 Cov.: 33 AF XY: 0.00000147 AC XY: 1 AN XY: 678174

African (AFR) AF: 0.0000349 AC: 1 AN: 28668

American (AMR) AF: 0.00 AC: 0 AN: 35556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24340

East Asian (EAS) AF: 0.00 AC: 0 AN: 33108

South Asian (SAS) AF: 0.00 AC: 0 AN: 77786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4588

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077486

Other (OTH) AF: 0.00 AC: 0 AN: 57258

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.49	T
Polyphen		0.13	B
Vest4		0.040
MutPred		0.45		Gain of disorder (P = 0.0429)
MVP		0.88
MPC		0.12
ClinPred		0.26	T
GERP RS		2.8
PromoterAI		0.0063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.071
gMVP		0.63

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

Other links and lift over

dbSNP: rs794729202; hg19: chr16-88923239;