chr16-88841077-T-A

Variant names:

• chr16-88841077-T-A
• rs118204438
• NM_000512.5:c.337A>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM5 PP5_Very_Strong

The NM_000512.5(GALNS):​c.337A>T​(p.Ile113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,612,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000399657: In vitro transient expression studies showed that the p.Ile113Phe variant reduced cDNA expression to approximately five percent of wild type (Tomatsu et al. 1995" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I113V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 2.31
• Publications: 30 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000399657: In vitro transient expression studies showed that the p.Ile113Phe variant reduced cDNA expression to approximately five percent of wild type (Tomatsu et al. 1995; Sukegawa et al. 2000).; SCV001547666: "In vivo and in vitro functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low in vitro enzymatic activity;"; SCV001581551: Experimental studies have shown that this missense change affects GALNS function (PMID: 7668283).; SCV000697064: Several publications report experimental evidence evaluating the effects of the variant on protein function. The most pronounced variant effect results in <10% of normal activity (Yamada_1998, Sukegawa_2000).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000512.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88841077-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2724611.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 16-88841077-T-A is Pathogenic according to our data. Variant chr16-88841077-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 703.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.337A>T	p.Ile113Phe	missense	Exon 4 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.355A>T	p.Ile119Phe	missense	Exon 5 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.-219A>T		5_prime_UTR	Exon 3 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.337A>T	p.Ile113Phe	missense	Exon 4 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.3746A>T		non_coding_transcript_exon	Exon 2 of 12
	GALNS	ENST00000565364.1	TSL:1	n.472A>T		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151808 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250884 AF XY: 0.0000515

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: 0.0000706

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1460844 Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111948

Other (OTH) AF: 0.000248 AC: 15 AN: 60386

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151808 Hom.: 0 Cov.: 33 AF XY: 0.0000540 AC XY: 4 AN XY: 74136

African (AFR) AF: 0.0000484 AC: 2 AN: 41338

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Mucopolysaccharidosis, MPS-IV-A (7)
1	-	-	Morquio syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	19
DANN	Benign	0.54
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.92	L
PhyloP100		2.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.024	D
Sift4G	Benign	0.29	T
Polyphen		0.99	D
Vest4		0.90
MVP		0.99
MPC		0.55
ClinPred		0.20	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.70
gMVP		0.93
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs118204438; hg19: chr16-88907485;