chr16-88824845-G-T

Variant names:

• chr16-88824845-G-T
• rs752339162
• NM_000512.5:c.1164C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000512.5(GALNS):​c.1164C>A​(p.Asp388Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D388N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.921
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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 chr16-88824847-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1048234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 16-88824845-G-T is Pathogenic according to our data. Variant chr16-88824845-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 528322.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.1164C>A	p.Asp388Glu	missense	Exon 11 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.1182C>A	p.Asp394Glu	missense	Exon 12 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.609C>A	p.Asp203Glu	missense	Exon 10 of 13	NP_001310472.1	Q6YL38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.1164C>A	p.Asp388Glu	missense	Exon 11 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4573C>A		non_coding_transcript_exon	Exon 9 of 12
	GALNS	ENST00000862787.1		c.1275C>A	p.Asp425Glu	missense	Exon 12 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249562 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461026 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726792

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Mucopolysaccharidosis, MPS-IV-A (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.92
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.24
Sift	Benign	0.18	T
Sift4G	Benign	0.17	T
Polyphen		0.38	B
Vest4		0.45
MutPred		0.69		Gain of sheet (P = 0.0344)
MVP		0.97
MPC		0.12
ClinPred		0.082	T
GERP RS		1.6
Varity_R		0.058
gMVP		0.77
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs752339162; hg19: chr16-88891253;