NM_000512.5:c.*520C>A

Variant names:

• chr16-88813919-G-T
• rs80125890
• NM_000512.5:c.*520C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000512.5(GALNS):​c.*520C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 196,570 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: GALNS NM_000512.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.96
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00331 (504/152204) while in subpopulation AFR AF = 0.0114 (473/41514). AF 95% confidence interval is 0.0105. There are 5 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.*520C>A		3_prime_UTR	Exon 14 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.*520C>A		3_prime_UTR	Exon 15 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.*520C>A		3_prime_UTR	Exon 13 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.*520C>A		3_prime_UTR	Exon 14 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.5498C>A		non_coding_transcript_exon	Exon 12 of 12
	GALNS	ENST00000862787.1		c.*520C>A		3_prime_UTR	Exon 15 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152086 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000293 AC: 13 AN: 44366 Hom.: 0 Cov.: 0 AF XY: 0.000256 AC XY: 6 AN XY: 23446

African (AFR) AF: 0.00671 AC: 11 AN: 1640

American (AMR) AF: 0.000276 AC: 1 AN: 3620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 914

East Asian (EAS) AF: 0.00 AC: 0 AN: 3148

South Asian (SAS) AF: 0.00 AC: 0 AN: 6424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 25004

Other (OTH) AF: 0.000454 AC: 1 AN: 2204

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152204 Hom.: 5 Cov.: 33 AF XY: 0.00324 AC XY: 241 AN XY: 74422

African (AFR) AF: 0.0114 AC: 473 AN: 41514

American (AMR) AF: 0.00157 AC: 24 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000758 Hom.: 1

Bravo AF: 0.00370

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.13
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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: rs80125890; hg19: chr16-88880327;