rs142822371

chr16-88822706-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000512.5(GALNS):c.1247T>C(p.Ile416Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00148 in 1,611,568 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (7 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 7.07

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a disulfide_bond (size 111) in uniprot entity GALNS_HUMAN there are 58 pathogenic changes around while only 5 benign (92%) in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.05973822).
• BP6: Variant 16-88822706-A-G is Benign according to our data. Variant chr16-88822706-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321191.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.1247T>C	p.Ile416Thr	missense_variant	12/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.1247T>C	p.Ile416Thr	missense_variant	12/14	1	NM_000512.5	P1
GALNS	ENST00000562593.5	n.4656T>C		non_coding_transcript_exon_variant	10/12	1
GALNS	ENST00000567525.5	c.*718T>C		3_prime_UTR_variant, NMD_transcript_variant	10/12	2
GALNS	ENST00000568613.5	c.*1210T>C		3_prime_UTR_variant, NMD_transcript_variant	13/15	2

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000917 AC: 229 AN: 249798 Hom.: 3 AF XY: 0.00101 AC XY: 137 AN XY: 135552

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00154 AC: 2253 AN: 1459378 Hom.: 7 Cov.: 32 AF XY: 0.00154 AC XY: 1115 AN XY: 725998

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.00196

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74408

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000907

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000974 AC: 118

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 09, 2023

Variant summary: GALNS c.1247T>C (p.Ile416Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 249798 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.00092 vs 0.002), allowing no conclusion about variant significance. c.1247T>C has been reported in the literature in a homozygous individual affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Morrone_2014). These data indicate that the variant could be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24726177, 29140481). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments classifying the variant as uncertain significance (n=2) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Morquio syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

The c.1247T>C (p.Ile416Thr) variant has been identified in a homozygous state in one individual diagnosed with mucopolysaccharidosis, type IVA (Morrone et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00175 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Ile416Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type IV. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.52	N
REVEL	Pathogenic	0.71
Sift	Benign	0.31	T
Sift4G	Benign	0.49	T
Polyphen		0.010	B
Vest4		0.46
MVP		0.94
MPC		0.13
ClinPred		0.025	T
GERP RS		3.8
Varity_R		0.052
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs142822371; hg19: chr16-88889114;