rs12934499

Variant names:

• chr16-88835868-C-T
• rs12934499
• NM_000512.5:c.634-19G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-88835868-C-T
• chr16-88835868-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000512.5(GALNS):​c.634-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,613,322 control chromosomes in the GnomAD database, including 54,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.22 (4427 hom., cov: 33)
  • Exomes 𝑓: 0.25 (49998 hom.)
• Consequence: GALNS NM_000512.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.65
• Publications: 13 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-88835868-C-T is Benign according to our data. Variant chr16-88835868-C-T is described in ClinVar as Benign. ClinVar VariationId is 93181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.634-19G>A		intron	N/A	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.652-19G>A		intron	N/A	NP_001310473.1
	GALNS	NM_001323543.2		c.79-19G>A		intron	N/A	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.634-19G>A		intron	N/A	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4043-19G>A		intron	N/A
	GALNS	ENST00000862787.1		c.745-19G>A		intron	N/A	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33257 AN: 152126 Hom.: 4434 Cov.: 33

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.271 AC: 67856 AN: 250784 AF XY: 0.272

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.570

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.254 AC: 370593 AN: 1461076 Hom.: 49998 Cov.: 43 AF XY: 0.255 AC XY: 185639 AN XY: 726854

African (AFR) AF: 0.0751 AC: 2515 AN: 33472

American (AMR) AF: 0.282 AC: 12599 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6918 AN: 26126

East Asian (EAS) AF: 0.581 AC: 23071 AN: 39682

South Asian (SAS) AF: 0.274 AC: 23609 AN: 86212

European-Finnish (FIN) AF: 0.269 AC: 14254 AN: 52996

Middle Eastern (MID) AF: 0.327 AC: 1879 AN: 5742

European-Non Finnish (NFE) AF: 0.243 AC: 269745 AN: 1111770

Other (OTH) AF: 0.265 AC: 16003 AN: 60370

GnomAD4 genome AF: 0.218 AC: 33256 AN: 152246 Hom.: 4427 Cov.: 33 AF XY: 0.222 AC XY: 16485 AN XY: 74424

African (AFR) AF: 0.0809 AC: 3362 AN: 41556

American (AMR) AF: 0.242 AC: 3711 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 915 AN: 3470

East Asian (EAS) AF: 0.567 AC: 2933 AN: 5176

South Asian (SAS) AF: 0.276 AC: 1332 AN: 4824

European-Finnish (FIN) AF: 0.270 AC: 2855 AN: 10586

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17160 AN: 68008

Other (OTH) AF: 0.261 AC: 552 AN: 2116

Alfa AF: 0.238 Hom.: 877

Bravo AF: 0.214

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Mucopolysaccharidosis, MPS-IV-A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.37
PhyloP100		-1.7
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs12934499; hg19: chr16-88902276;