rs11862754

Positions:

chr16-88842751-G-T

Variant summary

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

The NM_000512.5(GALNS):c.199C>A(p.Leu67Met) variant causes a missense change. The variant allele was found at a frequency of 0.0179 in 1,612,930 control chromosomes in the GnomAD database, including 4,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 2182 hom., cov: 33)

Exomes 𝑓: 0.010 ( 2070 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.12

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 0 benign, 7 uncertain in NM_000512.5

BP4

Computational evidence support a benign effect (MetaRNN=0.012288243).

BP6

Variant 16-88842751-G-T is Benign according to our data. Variant chr16-88842751-G-T is described in ClinVar as [Benign]. Clinvar id is 93172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88842751-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 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.199C>A	p.Leu67Met	missense_variant	2/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10 linkuse as main transcript	c.199C>A	p.Leu67Met	missense_variant	2/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0931

AC:

14157

AN:

152132

Hom.:

2175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0346

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.0575

GnomAD3 exomes

AF:

0.0243

AC:

6022

AN:

247650

Hom.:

829

AF XY:

0.0178

AC XY:

2395

AN XY:

134356

show subpopulations

Gnomad AFR exome

AF:

0.330

Gnomad AMR exome

AF:

0.0155

Gnomad ASJ exome

AF:

0.00896

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.000463

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0100

AC:

14616

AN:

1460680

Hom.:

2070

Cov.:

AF XY:

0.00874

AC XY:

6351

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.340

Gnomad4 AMR exome

AF:

0.0173

Gnomad4 ASJ exome

AF:

0.00920

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000686

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000589

Gnomad4 OTH exome

AF:

0.0230

GnomAD4 genome

AF:

0.0932

AC:

14190

AN:

152250

Hom.:

2182

Cov.:

AF XY:

0.0890

AC XY:

6624

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.324

Gnomad4 AMR

AF:

0.0346

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.0569

Alfa

AF:

0.0212

Hom.:

723

Bravo

AF:

0.106

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.319

AC:

1403

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.0300

AC:

3640

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00125

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2017	Variant summary: The GALNS c.199C>A (p.Leu67Met) variant located in the Sulfatase, N-terminal (InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 8588/274128 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.327481 (7722/23580). This frequency is about 160 times the estimated maximal expected allele frequency of a pathogenic GALNS variant (0.0020412), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. A publication, Laradi_2006 found the variant of interest to co-occur with pathogenic GALNS variants. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Mucopolysaccharidosis, MPS-IV-A

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	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); 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	Invitae	Jan 31, 2024	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.093

DEOGEN2

Uncertain

0.53

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.46

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.015

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.45

PROVEAN

Benign

0.81

REVEL

Uncertain

0.39

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.072

MPC

0.094

ClinPred

0.0016

GERP RS

3.9

Varity_R

0.15

gMVP

0.81

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