Genetic Variant GALNS:p.Ala231Gly (chr16-88835791-G-C) – 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.692C>G(p.Ala231Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0553 in 1,614,094 control chromosomes in the GnomAD database, including 2,937 homozygotes. In-silico tool predicts 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. A231V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.049 ( 244 hom., cov: 33)

Exomes 𝑓: 0.056 ( 2693 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 9.52

Publications

18 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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000512.5

BP4

Computational evidence support a benign effect (MetaRNN=0.004372239).

BP6

Variant 16-88835791-G-C is Benign according to our data. Variant chr16-88835791-G-C is described in ClinVar as Benign. ClinVar VariationId is 93183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0743 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.692C>G	p.Ala231Gly	missense	Exon 7 of 14	NP_000503.1	P34059
GALNS	NM_001323544.2		c.710C>G	p.Ala237Gly	missense	Exon 8 of 15	NP_001310473.1
GALNS	NM_001323543.2		c.137C>G	p.Ala46Gly	missense	Exon 6 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.692C>G	p.Ala231Gly	missense	Exon 7 of 14	ENSP00000268695.5	P34059
GALNS	ENST00000562593.5	TSL:1	n.4101C>G		non_coding_transcript_exon	Exon 5 of 12
GALNS	ENST00000862787.1		c.803C>G	p.Ala268Gly	missense	Exon 8 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes

AF:

0.0495

AC:

7535

AN:

152204

Hom.:

243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0340

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0808

Gnomad FIN

AF:

0.0229

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.0606

Gnomad OTH

AF:

0.0588

GnomAD2 exomes

AF:

0.0519

AC:

13037

AN:

251332

AF XY:

0.0548

show subpopulations

Gnomad AFR exome

AF:

0.0356

Gnomad AMR exome

AF:

0.0339

Gnomad ASJ exome

AF:

0.123

Gnomad EAS exome

AF:

0.000489

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.0599

Gnomad OTH exome

AF:

0.0607

GnomAD4 exome

AF:

0.0559

AC:

81652

AN:

1461772

Hom.:

2693

Cov.:

AF XY:

0.0575

AC XY:

41784

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0361

AC:

1207

AN:

33480

American (AMR)

AF:

0.0386

AC:

1725

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

3278

AN:

26132

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0811

AC:

6996

AN:

86250

European-Finnish (FIN)

AF:

0.0234

AC:

1248

AN:

53354

Middle Eastern (MID)

AF:

0.107

AC:

618

AN:

5766

European-Non Finnish (NFE)

AF:

0.0568

AC:

63214

AN:

1111976

Other (OTH)

AF:

0.0557

AC:

3361

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4526

9051

13577

18102

22628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2336

4672

7008

9344

11680

<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:

0.0494

AC:

7529

AN:

152322

Hom.:

244

Cov.:

AF XY:

0.0484

AC XY:

3606

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0338

AC:

1406

AN:

41564

American (AMR)

AF:

0.0490

AC:

750

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

415

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.0809

AC:

391

AN:

4834

European-Finnish (FIN)

AF:

0.0229

AC:

243

AN:

10630

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0606

AC:

4121

AN:

68018

Other (OTH)

AF:

0.0582

AC:

123

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

386

772

1158

1544

1930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0484

Hom.:

Bravo

AF:

0.0496

TwinsUK

AF:

0.0550

AC:

204

ALSPAC

AF:

0.0592

AC:

228

ESP6500AA

AF:

0.0369

AC:

162

ESP6500EA

AF:

0.0607

AC:

522

ExAC

AF:

0.0517

AC:

6271

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

EpiCase

AF:

0.0656

EpiControl

AF:

0.0644

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis, MPS-IV-A (4)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0044

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.085

PhyloP100

9.5

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.60

Sift

Uncertain

0.015

Sift4G

Uncertain

0.042

Polyphen

0.63

Vest4

0.28

MPC

0.39

ClinPred

0.023

GERP RS

5.0

Varity_R

0.80

gMVP

0.91

Mutation Taster

=29/71

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over