16-88836222-G-C

Variant names:

• chr16-88836222-G-C
• rs118204435
• NM_000512.5:c.612C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000512.5(GALNS):​c.612C>G​(p.Asn204Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,454 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: "SCV001547754: "In vivo and in vitro 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. N204T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.89
• Publications: 12 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]

GALNS Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 4A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001547754: "In vivo and in vitro functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_moderate);"
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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 chr16-88836223-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1048418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant 16-88836222-G-C is Pathogenic according to our data. Variant chr16-88836222-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 698.Status of the report is criteria_provided_single_submitter, 1 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.612C>G	p.Asn204Lys	missense	Exon 6 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.630C>G	p.Asn210Lys	missense	Exon 7 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.57C>G	p.Asn19Lys	missense	Exon 5 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.612C>G	p.Asn204Lys	missense	Exon 6 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4021C>G		non_coding_transcript_exon	Exon 4 of 12
	GALNS	ENST00000862787.1		c.723C>G	p.Asn241Lys	missense	Exon 7 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461210 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726938

⚠️ 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: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111822

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

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

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis, MPS-IV-A (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.60	N
PhyloP100		3.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.42
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.78	P
Vest4		0.92
MutPred		0.88		Gain of ubiquitination at N204 (P = 0.0198)
MVP		0.94
MPC		0.31
ClinPred		0.70	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs118204435; hg19: chr16-88902630;