16-88835869-G-A

Variant names:

• chr16-88835869-G-A
• rs17603837
• NM_000512.5:c.634-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000512.5(GALNS):​c.634-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0935 in 1,613,416 control chromosomes in the GnomAD database, including 7,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.091 (695 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7112 hom.)
• Consequence: GALNS NM_000512.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.72
• Publications: 10 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-88835869-G-A is Benign according to our data. Variant chr16-88835869-G-A is described in ClinVar as Benign. ClinVar VariationId is 93182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.152 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.634-20C>T		intron	N/A	NP_000503.1
	GALNS	NM_001323544.2		c.652-20C>T		intron	N/A	NP_001310473.1
	GALNS	NM_001323543.2		c.79-20C>T		intron	N/A	NP_001310472.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.634-20C>T		intron	N/A	ENSP00000268695.5
	GALNS	ENST00000562593.5	TSL:1	n.4043-20C>T		intron	N/A
	GALNS	ENST00000562831.1	TSL:3	c.418-20C>T		intron	N/A	ENSP00000455174.1

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13769 AN: 152178 Hom.: 692 Cov.: 33

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.0965

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0981 AC: 24607 AN: 250874 AF XY: 0.103

Gnomad AFR exome AF: 0.0758

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0351

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0997

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0938 AC: 137095 AN: 1461120 Hom.: 7112 Cov.: 35 AF XY: 0.0966 AC XY: 70207 AN XY: 726854

African (AFR) AF: 0.0744 AC: 2491 AN: 33464

American (AMR) AF: 0.106 AC: 4756 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4158 AN: 26128

East Asian (EAS) AF: 0.0418 AC: 1660 AN: 39696

South Asian (SAS) AF: 0.156 AC: 13409 AN: 86212

European-Finnish (FIN) AF: 0.0457 AC: 2423 AN: 53012

Middle Eastern (MID) AF: 0.165 AC: 944 AN: 5736

European-Non Finnish (NFE) AF: 0.0914 AC: 101572 AN: 1111788

Other (OTH) AF: 0.0941 AC: 5682 AN: 60366

GnomAD4 genome AF: 0.0905 AC: 13787 AN: 152296 Hom.: 695 Cov.: 33 AF XY: 0.0901 AC XY: 6708 AN XY: 74478

African (AFR) AF: 0.0733 AC: 3048 AN: 41566

American (AMR) AF: 0.121 AC: 1854 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 542 AN: 3468

East Asian (EAS) AF: 0.0314 AC: 163 AN: 5188

South Asian (SAS) AF: 0.161 AC: 777 AN: 4822

European-Finnish (FIN) AF: 0.0418 AC: 444 AN: 10620

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.0965 AC: 6565 AN: 68008

Other (OTH) AF: 0.108 AC: 228 AN: 2116

Alfa AF: 0.0968 Hom.: 203

Bravo AF: 0.0934

Asia WGS AF: 0.0980 AC: 338 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.40
DANN	Benign	0.45
PhyloP100		-1.7
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs17603837; hg19: chr16-88902277;