rs142822371

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.07

Publications

3 publications found

Variant links:

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

GALNS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

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 VariationId is 321191.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5 link	c.1247T>C	p.Ile416Thr	missense_variant	Exon 12 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10 link	c.1247T>C	p.Ile416Thr	missense_variant	Exon 12 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes

AF:

0.000901

AC:

137

AN:

152072

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000917

AC:

229

AN:

249798

AF XY:

0.00101

show subpopulations

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 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.:

Cov.:

AF XY:

0.00154

AC XY:

1115

AN XY:

725998

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33436

American (AMR)

AF:

0.000426

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.00147

AC:

127

AN:

86196

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

52428

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00178

AC:

1972

AN:

1110968

Other (OTH)

AF:

0.00196

AC:

118

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

127

253

380

506

633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000900

AC:

137

AN:

152190

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41534

American (AMR)

AF:

0.000523

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

67986

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00112

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000974

AC:

118

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Uncertain:1Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2021

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting)

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

May 09, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.9

PhyloP100

7.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.52

REVEL

Pathogenic

0.71

Sift

Benign

0.31

Sift4G

Benign

0.49

Vest4

0.46

ClinPred

0.025

GERP RS

3.8

Varity_R

0.052

gMVP

0.82

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over