chr16-88837646-T-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000512.5(GALNS):​c.542A>T​(p.Tyr181Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y181C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

1
10
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.94

Publications

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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000512.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-88837646-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192298.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GALNSNM_000512.5 linkc.542A>T p.Tyr181Phe missense_variant Exon 5 of 14 ENST00000268695.10 NP_000503.1 P34059Q96I49

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GALNSENST00000268695.10 linkc.542A>T p.Tyr181Phe missense_variant Exon 5 of 14 1 NM_000512.5 ENSP00000268695.5 P34059

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461484
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727070
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86238
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53270
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5586
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111988
Other (OTH)
AF:
0.00
AC:
0
AN:
60370
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.69
D;.
Eigen
Benign
-0.085
Eigen_PC
Benign
-0.025
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Uncertain
0.53
D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Benign
0.67
N;.
PhyloP100
5.9
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-1.5
N;N
REVEL
Uncertain
0.51
Sift
Benign
0.16
T;T
Sift4G
Benign
0.39
T;.
Polyphen
0.95
P;.
Vest4
0.50
MutPred
0.52
Loss of phosphorylation at Y181 (P = 0.0484);.;
MVP
0.91
MPC
0.11
ClinPred
0.70
D
GERP RS
2.8
Varity_R
0.49
gMVP
0.82
Mutation Taster
=47/53
disease causing

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

Other links and lift over

dbSNP: rs786205899; hg19: chr16-88904054; API