rs35232749

Variant names:

• chr16-88835265-G-A
• rs35232749
• NM_000512.5:c.846C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000512.5(GALNS):​c.846C>T​(p.Phe282Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,610,646 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (147 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1274 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0650
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-88835265-G-A is Benign according to our data. Variant chr16-88835265-G-A is described in ClinVar as Benign. ClinVar VariationId is 93187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.065 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0768 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.846C>T	p.Phe282Phe	synonymous	Exon 8 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.864C>T	p.Phe288Phe	synonymous	Exon 9 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.291C>T	p.Phe97Phe	synonymous	Exon 7 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.846C>T	p.Phe282Phe	synonymous	Exon 8 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4255C>T		non_coding_transcript_exon	Exon 6 of 12
	GALNS	ENST00000862787.1		c.957C>T	p.Phe319Phe	synonymous	Exon 9 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5941 AN: 152142 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0458 AC: 11223 AN: 245130 AF XY: 0.0475

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.0343

Gnomad EAS exome AF: 0.0346

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0396

Gnomad OTH exome AF: 0.0447

GnomAD4 exome AF: 0.0383 AC: 55806 AN: 1458386 Hom.: 1274 Cov.: 33 AF XY: 0.0395 AC XY: 28617 AN XY: 725128

African (AFR) AF: 0.0306 AC: 1022 AN: 33442

American (AMR) AF: 0.0669 AC: 2960 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 871 AN: 25944

East Asian (EAS) AF: 0.0416 AC: 1651 AN: 39648

South Asian (SAS) AF: 0.0777 AC: 6643 AN: 85448

European-Finnish (FIN) AF: 0.0226 AC: 1201 AN: 53206

Middle Eastern (MID) AF: 0.0562 AC: 324 AN: 5762

European-Non Finnish (NFE) AF: 0.0350 AC: 38837 AN: 1110428

Other (OTH) AF: 0.0381 AC: 2297 AN: 60268

GnomAD4 genome AF: 0.0391 AC: 5958 AN: 152260 Hom.: 147 Cov.: 32 AF XY: 0.0398 AC XY: 2964 AN XY: 74448

African (AFR) AF: 0.0319 AC: 1325 AN: 41556

American (AMR) AF: 0.0714 AC: 1093 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3468

East Asian (EAS) AF: 0.0301 AC: 156 AN: 5182

South Asian (SAS) AF: 0.0836 AC: 402 AN: 4810

European-Finnish (FIN) AF: 0.0191 AC: 203 AN: 10614

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0361 AC: 2455 AN: 68006

Other (OTH) AF: 0.0482 AC: 102 AN: 2116

Alfa AF: 0.0385 Hom.: 107

Bravo AF: 0.0413

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.67
DANN	Benign	0.58
PhyloP100		0.065
Mutation Taster		=100/0	polymorphism (auto)

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: rs35232749; hg19: chr16-88901673; COSMIC: COSV51938722; COSMIC: COSV51938722;