Genetic Variant NM_000512.5:c.1502G>A (chr16-88814506-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000512.5(GALNS):c.1502G>A(p.Cys501Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C501S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.56

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr16-88814506-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1048343.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 16-88814506-C-T is Pathogenic according to our data. Variant chr16-88814506-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522756.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNS	NM_000512.5	MANE Select	c.1502G>A	p.Cys501Tyr	missense	Exon 14 of 14	NP_000503.1
GALNS	NM_001323544.2		c.1520G>A	p.Cys507Tyr	missense	Exon 15 of 15	NP_001310473.1
GALNS	NM_001323543.2		c.947G>A	p.Cys316Tyr	missense	Exon 13 of 13	NP_001310472.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNS	ENST00000268695.10	TSL:1 MANE Select	c.1502G>A	p.Cys501Tyr	missense	Exon 14 of 14	ENSP00000268695.5
GALNS	ENST00000562593.5	TSL:1	n.4911G>A		non_coding_transcript_exon	Exon 12 of 12
GALNS	ENST00000567525.5	TSL:2	n.*973G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000454484.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694396

African (AFR)

AF:

0.00

AC:

AN:

32170

American (AMR)

AF:

0.00

AC:

AN:

36496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25240

East Asian (EAS)

AF:

0.00

AC:

AN:

36922

South Asian (SAS)

AF:

0.00

AC:

AN:

79754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5536

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082678

Other (OTH)

AF:

0.00

AC:

AN:

58272

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Pathogenic:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.6

PhyloP100

6.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.88

MutPred

0.84

Gain of phosphorylation at C501 (P = 0.0814)

MVP

1.0

MPC

0.65

ClinPred

1.0

GERP RS

5.1

Varity_R

0.91

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over