rs2303269

Positions:

chr16-88824832-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000512.5(GALNS):c.1177G>T(p.Ala393Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0521 in 1,613,270 control chromosomes in the GnomAD database, including 2,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 257 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2225 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.60

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000512.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0041275322).

BP6

Variant 16-88824832-C-A is Benign according to our data. Variant chr16-88824832-C-A is described in ClinVar as [Benign]. Clinvar id is 93165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5 linkuse as main transcript	c.1177G>T	p.Ala393Ser	missense_variant	11/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10 linkuse as main transcript	c.1177G>T	p.Ala393Ser	missense_variant	11/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0535

AC:

8146

AN:

152184

Hom.:

256

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0417

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.0819

Gnomad ASJ

AF:

0.0498

Gnomad EAS

AF:

0.0574

Gnomad SAS

AF:

0.0936

Gnomad FIN

AF:

0.0593

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.0632

GnomAD3 exomes

AF:

0.0617

AC:

15403

AN:

249724

Hom.:

529

AF XY:

0.0635

AC XY:

8594

AN XY:

135442

show subpopulations

Gnomad AFR exome

AF:

0.0410

Gnomad AMR exome

AF:

0.0774

Gnomad ASJ exome

AF:

0.0479

Gnomad EAS exome

AF:

0.0604

Gnomad SAS exome

AF:

0.0894

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0548

Gnomad OTH exome

AF:

0.0596

GnomAD4 exome

AF:

0.0520

AC:

75920

AN:

1460968

Hom.:

2225

Cov.:

AF XY:

0.0530

AC XY:

38486

AN XY:

726746

show subpopulations

Gnomad4 AFR exome

AF:

0.0400

Gnomad4 AMR exome

AF:

0.0767

Gnomad4 ASJ exome

AF:

0.0460

Gnomad4 EAS exome

AF:

0.0678

Gnomad4 SAS exome

AF:

0.0883

Gnomad4 FIN exome

AF:

0.0561

Gnomad4 NFE exome

AF:

0.0478

Gnomad4 OTH exome

AF:

0.0530

GnomAD4 genome

AF:

0.0536

AC:

8165

AN:

152302

Hom.:

257

Cov.:

AF XY:

0.0553

AC XY:

4118

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0418

Gnomad4 AMR

AF:

0.0823

Gnomad4 ASJ

AF:

0.0498

Gnomad4 EAS

AF:

0.0570

Gnomad4 SAS

AF:

0.0937

Gnomad4 FIN

AF:

0.0593

Gnomad4 NFE

AF:

0.0495

Gnomad4 OTH

AF:

0.0640

Alfa

AF:

0.0502

Hom.:

126

Bravo

AF:

0.0535

TwinsUK

AF:

0.0472

AC:

175

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.0434

AC:

191

ESP6500EA

AF:

0.0493

AC:

424

ExAC

AF:

0.0615

AC:

7463

Asia WGS

AF:

0.0820

AC:

286

AN:

3478

EpiCase

AF:

0.0512

EpiControl

AF:

0.0524

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	Allele frequency is >5% in gnomAD v2.1.1 (BA1_stand-alone); allele frequency is greater than expected for disorder (BS1_strong); multiple lines of computational evidence suggest no impact on gene or gene product (BP4_supporting) -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2019	Variant summary: GALNS c.1177G>T (p.Ala393Ser) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.06 in 275882 control chromosomes in the gnomAD database, including 553 homozygotes. The observed variant frequency is approximately 29-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) phenotype (0.002), strongly suggesting that the variant is benign. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	This variant is associated with the following publications: (PMID: 25252036, 24035930, 16837223, 21251309, 15235041, 15241807, 9452036) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.69

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.72

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Uncertain

0.014

Sift4G

Benign

0.082

Polyphen

0.020

Vest4

0.11

MPC

0.091

ClinPred

0.021

GERP RS

1.6

Varity_R

0.16

gMVP

0.84

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over