NM_000512.5:c.*236C>T

Variant names:

• chr16-88814203-G-A
• rs189375208
• NM_000512.5:c.*236C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000512.5(GALNS):​c.*236C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 601,032 control chromosomes in the GnomAD database, including 41 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 0.0067 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (36 hom.)
• Consequence: GALNS NM_000512.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.663
• Publications: 0 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=-0.87).
• BP6: Variant 16-88814203-G-A is Benign according to our data. Variant chr16-88814203-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 321180.
• 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.*236C>T		3_prime_UTR	Exon 14 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.*236C>T		3_prime_UTR	Exon 15 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.*236C>T		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.*236C>T		3_prime_UTR	Exon 14 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.5214C>T		non_coding_transcript_exon	Exon 12 of 12
	GALNS	ENST00000862787.1		c.*236C>T		3_prime_UTR	Exon 15 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 1018 AN: 152100 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.00805 AC: 3613 AN: 448814 Hom.: 36 Cov.: 4 AF XY: 0.00753 AC XY: 1789 AN XY: 237684

African (AFR) AF: 0.00167 AC: 21 AN: 12590

American (AMR) AF: 0.00147 AC: 30 AN: 20472

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 175 AN: 13812

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29884

South Asian (SAS) AF: 0.0000848 AC: 4 AN: 47150

European-Finnish (FIN) AF: 0.0235 AC: 656 AN: 27940

Middle Eastern (MID) AF: 0.000518 AC: 1 AN: 1932

European-Non Finnish (NFE) AF: 0.00935 AC: 2519 AN: 269298

Other (OTH) AF: 0.00800 AC: 206 AN: 25736

GnomAD4 genome AF: 0.00669 AC: 1018 AN: 152218 Hom.: 5 Cov.: 33 AF XY: 0.00657 AC XY: 489 AN XY: 74418

African (AFR) AF: 0.00152 AC: 63 AN: 41528

American (AMR) AF: 0.00105 AC: 16 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0101 AC: 685 AN: 68004

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00759 Hom.: 0

Bravo AF: 0.00528

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Morquio syndrome (1)
-	-	1	Mucopolysaccharidosis, MPS-IV-A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.51
PhyloP100		-0.66
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: rs189375208; hg19: chr16-88880611; COSMIC: COSV108045547; COSMIC: COSV108045547;