rs7187889

Variant names:

• chr16-88836235-G-A
• rs7187889
• NM_000512.5:c.599C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-88836235-G-A
• chr16-88836235-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000512.5(GALNS):​c.599C>T​(p.Thr200Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,613,198 control chromosomes in the GnomAD database, including 842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T200T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (447 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (395 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.48
• Publications: 8 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 -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019369423).
• BP6: Variant 16-88836235-G-A is Benign according to our data. Variant chr16-88836235-G-A is described in ClinVar as Benign. ClinVar VariationId is 198087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 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.599C>T	p.Thr200Met	missense	Exon 6 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.617C>T	p.Thr206Met	missense	Exon 7 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.44C>T	p.Thr15Met	missense	Exon 5 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.599C>T	p.Thr200Met	missense	Exon 6 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4008C>T		non_coding_transcript_exon	Exon 4 of 12
	GALNS	ENST00000862787.1		c.710C>T	p.Thr237Met	missense	Exon 7 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6288 AN: 152196 Hom.: 445 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0109 AC: 2720 AN: 250494 AF XY: 0.00799

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00738

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00437 AC: 6388 AN: 1460884 Hom.: 395 Cov.: 32 AF XY: 0.00382 AC XY: 2773 AN XY: 726774

African (AFR) AF: 0.152 AC: 5074 AN: 33412

American (AMR) AF: 0.00846 AC: 378 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5764

European-Non Finnish (NFE) AF: 0.000293 AC: 326 AN: 1111694

Other (OTH) AF: 0.00909 AC: 549 AN: 60372

GnomAD4 genome AF: 0.0414 AC: 6307 AN: 152314 Hom.: 447 Cov.: 33 AF XY: 0.0396 AC XY: 2946 AN XY: 74478

African (AFR) AF: 0.144 AC: 5970 AN: 41540

American (AMR) AF: 0.0158 AC: 242 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68034

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0110 Hom.: 146

Bravo AF: 0.0478

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.146 AC: 643

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0134 AC: 1628

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Mucopolysaccharidosis, MPS-IV-A (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.027	D
Sift4G	Benign	0.089	T
Polyphen		0.93	P
Vest4		0.26
MPC		0.23
ClinPred		0.053	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.75
Mutation Taster		=26/74	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: rs7187889; hg19: chr16-88902643;