dbSNP rs114703967: GALNS:p.Ala459Val (chr16-88818113-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000512.5(GALNS):c.1376C>T(p.Ala459Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,573,198 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A459T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 256 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 286 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.266

Publications

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

GALNS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000512.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0017710924).

BP6

Variant 16-88818113-G-A is Benign according to our data. Variant chr16-88818113-G-A is described in ClinVar as Benign. ClinVar VariationId is 321189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

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	UniProt
GALNS	NM_000512.5	MANE Select	c.1376C>T	p.Ala459Val	missense	Exon 13 of 14	NP_000503.1	P34059
GALNS	NM_001323544.2		c.1394C>T	p.Ala465Val	missense	Exon 14 of 15	NP_001310473.1
GALNS	NM_001323543.2		c.821C>T	p.Ala274Val	missense	Exon 12 of 13	NP_001310472.1	Q6YL38

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALNS	ENST00000268695.10	TSL:1 MANE Select	c.1376C>T	p.Ala459Val	missense	Exon 13 of 14	ENSP00000268695.5	P34059
GALNS	ENST00000562593.5	TSL:1	n.4785C>T		non_coding_transcript_exon	Exon 11 of 12
GALNS	ENST00000862787.1		c.1487C>T	p.Ala496Val	missense	Exon 14 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4932

AN:

152146

Hom.:

256

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.00912

AC:

1761

AN:

193128

AF XY:

0.00633

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.00648

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000113

Gnomad NFE exome

AF:

0.000395

Gnomad OTH exome

AF:

0.00431

GnomAD4 exome

AF:

0.00352

AC:

5008

AN:

1420934

Hom.:

286

Cov.:

AF XY:

0.00301

AC XY:

2120

AN XY:

704400

show subpopulations

African (AFR)

AF:

0.121

AC:

4016

AN:

33216

American (AMR)

AF:

0.00644

AC:

253

AN:

39286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25450

East Asian (EAS)

AF:

0.00

AC:

AN:

38682

South Asian (SAS)

AF:

0.000208

AC:

AN:

81692

European-Finnish (FIN)

AF:

0.0000259

AC:

AN:

38582

Middle Eastern (MID)

AF:

0.00355

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.000234

AC:

257

AN:

1099028

Other (OTH)

AF:

0.00748

AC:

444

AN:

59360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

228

455

683

910

1138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.0324

AC:

4940

AN:

152264

Hom.:

256

Cov.:

AF XY:

0.0311

AC XY:

2319

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.113

AC:

4710

AN:

41518

American (AMR)

AF:

0.00948

AC:

145

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68028

Other (OTH)

AF:

0.0255

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

229

459

688

918

1147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.00878

Hom.:

Bravo

AF:

0.0374

ESP6500AA

AF:

0.113

AC:

494

ESP6500EA

AF:

0.000701

AC:

ExAC

AF:

0.00939

AC:

1122

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis, MPS-IV-A (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.5

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.74

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

PhyloP100

-0.27

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.1

REVEL

Benign

0.11

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.047

Vest4

0.12

MVP

0.74

MPC

0.097

ClinPred

0.0036

GERP RS

-4.9

Varity_R

0.070

gMVP

0.33

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over