rs140299014

Variant names:

• chr16-88835253-C-T
• rs140299014
• NM_000512.5:c.858G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-88835253-C-T
• chr16-88835253-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000512.5(GALNS):​c.858G>A​(p.Thr286Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,607,482 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.37
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-88835253-C-T is Benign according to our data. Variant chr16-88835253-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256337.
• BP7: Synonymous conserved (PhyloP=-2.37 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.858G>A	p.Thr286Thr	synonymous	Exon 8 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.876G>A	p.Thr292Thr	synonymous	Exon 9 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.303G>A	p.Thr101Thr	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.858G>A	p.Thr286Thr	synonymous	Exon 8 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4267G>A		non_coding_transcript_exon	Exon 6 of 12
	GALNS	ENST00000862787.1		c.969G>A	p.Thr323Thr	synonymous	Exon 9 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000604 AC: 145 AN: 240034 AF XY: 0.000593

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.00162 AC: 2362 AN: 1455206 Hom.: 2 Cov.: 32 AF XY: 0.00161 AC XY: 1161 AN XY: 723238

African (AFR) AF: 0.000269 AC: 9 AN: 33418

American (AMR) AF: 0.000182 AC: 8 AN: 43848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.0000824 AC: 7 AN: 84952

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00202 AC: 2238 AN: 1108714

Other (OTH) AF: 0.00165 AC: 99 AN: 60162

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74460

African (AFR) AF: 0.000385 AC: 16 AN: 41538

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.000691

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Mucopolysaccharidosis, MPS-IV-A (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.022
DANN	Benign	0.70
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs140299014; hg19: chr16-88901661; COSMIC: COSV51940935; COSMIC: COSV51940935;