16-88856757-C-G

Variant names:

• chr16-88856757-C-G
• rs911877265
• NM_000512.5:c.120+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000512.5(GALNS):​c.120+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALNS NM_000512.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.13
• Publications: 2 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

LOC107983950 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-88856757-C-G is Pathogenic according to our data. Variant chr16-88856757-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 847816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.120+1G>C		splice_donor intron	N/A	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.-33+1G>C		splice_donor intron	N/A	NP_001310473.1
	GALNS	NM_001323543.2		c.-312+1G>C		splice_donor intron	N/A	NP_001310472.1	Q6YL38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.120+1G>C		splice_donor intron	N/A	ENSP00000268695.5	P34059
	GALNS	ENST00000568311.1	TSL:1	c.120+1G>C		splice_donor intron	N/A	ENSP00000455006.1	H3BNU2
	TRAPPC2L	ENST00000564365.5	TSL:1	c.-398+511C>G		intron	N/A	ENSP00000455447.1	H3BPS1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000690 AC: 1 AN: 144998 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000145 AC: 2 AN: 1375962 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 679062

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30868

American (AMR) AF: 0.0000272 AC: 1 AN: 36756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24562

East Asian (EAS) AF: 0.00 AC: 0 AN: 35430

South Asian (SAS) AF: 0.00 AC: 0 AN: 79004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074298

Other (OTH) AF: 0.00 AC: 0 AN: 57150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis, MPS-IV-A (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.1
GERP RS		3.5
PromoterAI		-0.020	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -12
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs911877265; hg19: chr16-88923165;