rs755832705

Variant names:

• chr16-88856771-A-C
• rs755832705
• NM_000512.5:c.107T>G

Your query was ambiguous. Multiple possible variants found:

• chr16-88856771-A-C
• chr16-88856771-A-G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000512.5(GALNS):​c.107T>G​(p.Leu36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,387,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001547581: "In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L36P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.39
• Publications: 7 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001547581: "In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_moderate);"; SCV005061198: Experimental studies showed damaging effect on the gene product (Caciotti A, et. al., 2015; Zanetti A, et. al., 2021).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000512.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88856771-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1048256.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 16-88856771-A-C is Pathogenic according to our data. Variant chr16-88856771-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 528320.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.107T>G	p.Leu36Arg	missense	Exon 1 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.-46T>G		5_prime_UTR	Exon 1 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.-325T>G		5_prime_UTR	Exon 1 of 13	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.107T>G	p.Leu36Arg	missense	Exon 1 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000568311.1	TSL:1	c.107T>G	p.Leu36Arg	missense	Exon 1 of 3	ENSP00000455006.1	H3BNU2
	TRAPPC2L	ENST00000564365.5	TSL:1	c.-398+525A>C		intron	N/A	ENSP00000455447.1	H3BPS1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000260 AC: 4 AN: 153974 AF XY: 0.0000468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 AF: 0.00000288 AC: 4 AN: 1387354 Hom.: 0 Cov.: 33 AF XY: 0.00000583 AC XY: 4 AN XY: 686108

African (AFR) AF: 0.00 AC: 0 AN: 31014

American (AMR) AF: 0.00 AC: 0 AN: 38382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24626

East Asian (EAS) AF: 0.00 AC: 0 AN: 35428

South Asian (SAS) AF: 0.0000501 AC: 4 AN: 79890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4246

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082494

Other (OTH) AF: 0.00 AC: 0 AN: 57594

GnomAD4 genome Cov.: 29

ExAC AF: 0.0000278 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely 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
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.85
MutPred		0.86		Loss of stability (P = 0.0345)
MVP		1.0
MPC		0.52
ClinPred		0.94	D
GERP RS		3.5
PromoterAI		0.031	Neutral
Varity_R		0.99
gMVP		0.98
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs755832705; hg19: chr16-88923179;