rs2303269

Variant names:

• chr16-88824832-C-A
• rs2303269
• NM_000512.5:c.1177G>T

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.1177G>T​(p.Ala393Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0521 in 1,613,270 control chromosomes in the GnomAD database, including 2,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.054 (257 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2225 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.60
• Publications: 22 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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0041275322).
• BP6: Variant 16-88824832-C-A is Benign according to our data. Variant chr16-88824832-C-A is described in ClinVar as Benign. ClinVar VariationId is 93165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0866 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.1177G>T	p.Ala393Ser	missense	Exon 11 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.1195G>T	p.Ala399Ser	missense	Exon 12 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.622G>T	p.Ala208Ser	missense	Exon 10 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.1177G>T	p.Ala393Ser	missense	Exon 11 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4586G>T		non_coding_transcript_exon	Exon 9 of 12
	GALNS	ENST00000862787.1		c.1288G>T	p.Ala430Ser	missense	Exon 12 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8146 AN: 152184 Hom.: 256 Cov.: 33

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.0574

Gnomad SAS AF: 0.0936

Gnomad FIN AF: 0.0593

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0617 AC: 15403 AN: 249724 AF XY: 0.0635

Gnomad AFR exome AF: 0.0410

Gnomad AMR exome AF: 0.0774

Gnomad ASJ exome AF: 0.0479

Gnomad EAS exome AF: 0.0604

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0548

Gnomad OTH exome AF: 0.0596

GnomAD4 exome AF: 0.0520 AC: 75920 AN: 1460968 Hom.: 2225 Cov.: 32 AF XY: 0.0530 AC XY: 38486 AN XY: 726746

African (AFR) AF: 0.0400 AC: 1339 AN: 33478

American (AMR) AF: 0.0767 AC: 3428 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0460 AC: 1203 AN: 26136

East Asian (EAS) AF: 0.0678 AC: 2693 AN: 39696

South Asian (SAS) AF: 0.0883 AC: 7620 AN: 86254

European-Finnish (FIN) AF: 0.0561 AC: 2952 AN: 52656

Middle Eastern (MID) AF: 0.0651 AC: 375 AN: 5764

European-Non Finnish (NFE) AF: 0.0478 AC: 53109 AN: 1111894

Other (OTH) AF: 0.0530 AC: 3201 AN: 60370

GnomAD4 genome AF: 0.0536 AC: 8165 AN: 152302 Hom.: 257 Cov.: 33 AF XY: 0.0553 AC XY: 4118 AN XY: 74466

African (AFR) AF: 0.0418 AC: 1739 AN: 41572

American (AMR) AF: 0.0823 AC: 1259 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 173 AN: 3472

East Asian (EAS) AF: 0.0570 AC: 295 AN: 5178

South Asian (SAS) AF: 0.0937 AC: 452 AN: 4824

European-Finnish (FIN) AF: 0.0593 AC: 630 AN: 10616

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3368 AN: 68026

Other (OTH) AF: 0.0640 AC: 135 AN: 2110

Alfa AF: 0.0513 Hom.: 173

Bravo AF: 0.0535

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.0434 AC: 191

ESP6500EA AF: 0.0493 AC: 424

ExAC AF: 0.0615 AC: 7463

Asia WGS AF: 0.0820 AC: 286 AN: 3478

EpiCase AF: 0.0512

EpiControl AF: 0.0524

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Mucopolysaccharidosis, MPS-IV-A (5)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Uncertain	0.014	D
Sift4G	Benign	0.082	T
Polyphen		0.020	B
Vest4		0.11
MPC		0.091
ClinPred		0.021	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.84
Mutation Taster		=95/5	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: rs2303269; hg19: chr16-88891240; COSMIC: COSV51936235;