Genetic Variant GALNS:p.His236Gln (chr16-88835775-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000512.5(GALNS):c.708C>A(p.His236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. H236R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.355

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

GALNS links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr16-88835776-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93185.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

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
GALNS	NM_000512.5	MANE Select	c.708C>A	p.His236Gln	missense	Exon 7 of 14	NP_000503.1
GALNS	NM_001323544.2		c.726C>A	p.His242Gln	missense	Exon 8 of 15	NP_001310473.1
GALNS	NM_001323543.2		c.153C>A	p.His51Gln	missense	Exon 6 of 13	NP_001310472.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNS	ENST00000268695.10	TSL:1 MANE Select	c.708C>A	p.His236Gln	missense	Exon 7 of 14	ENSP00000268695.5
GALNS	ENST00000562593.5	TSL:1	n.4117C>A		non_coding_transcript_exon	Exon 5 of 12
GALNS	ENST00000562831.1	TSL:3	c.492C>A	p.His164Gln	missense	Exon 6 of 6	ENSP00000455174.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

1.4

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.96

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

4.1

PhyloP100

-0.35

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.98

MutPred

0.88

Gain of sheet (P = 0.0266)

MVP

0.99

MPC

0.51

ClinPred

1.0

GERP RS

-4.9

Varity_R

0.91

gMVP

0.99

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over