dbSNP rs11862754: GALNS:p.Leu67Met (chr16-88842751-G-T) – 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.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. 13/21 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:12

Conservation

PhyloP100: 4.12

Publications

13 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 VariationId is 93172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 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.199C>A	p.Leu67Met	missense	Exon 2 of 14	NP_000503.1	P34059
GALNS	NM_001323544.2		c.217C>A	p.Leu73Met	missense	Exon 3 of 15	NP_001310473.1
GALNS	NM_001323543.2		c.-311-780C>A		intron	N/A	NP_001310472.1	Q6YL38

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALNS	ENST00000268695.10	TSL:1 MANE Select	c.199C>A	p.Leu67Met	missense	Exon 2 of 14	ENSP00000268695.5	P34059
GALNS	ENST00000562593.5	TSL:1	n.2874C>A		non_coding_transcript_exon	Exon 1 of 12
GALNS	ENST00000565364.1	TSL:1	n.334C>A		non_coding_transcript_exon	Exon 3 of 6

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

GnomAD2 exomes

AF:

0.0243

AC:

6022

AN:

247650

AF XY:

0.0178

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 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

African (AFR)

AF:

0.340

AC:

11389

AN:

33448

American (AMR)

AF:

0.0173

AC:

771

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.00920

AC:

240

AN:

26088

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.000686

AC:

AN:

86006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52948

Middle Eastern (MID)

AF:

0.0198

AC:

114

AN:

5764

European-Non Finnish (NFE)

AF:

0.000589

AC:

655

AN:

1111778

Other (OTH)

AF:

0.0230

AC:

1387

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

598

1195

1793

2390

2988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.0932

AC:

14190

AN:

152250

Hom.:

2182

Cov.:

AF XY:

0.0890

AC XY:

6624

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.324

AC:

13428

AN:

41508

American (AMR)

AF:

0.0346

AC:

529

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68018

Other (OTH)

AF:

0.0569

AC:

120

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

514

1029

1543

2058

2572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.0377

Hom.:

1765

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Mucopolysaccharidosis, MPS-IV-A (4)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

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

PhyloP100

4.1

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

Mutation Taster

=95/5

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