rs76095307

Variant names:

• chr16-88835171-C-G
• rs76095307
• NM_000512.5:c.898+42G>C

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.898+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0558 in 1,554,154 control chromosomes in the GnomAD database, including 2,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (271 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2618 hom.)
• Consequence: GALNS NM_000512.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.35
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-88835171-C-G is Benign according to our data. Variant chr16-88835171-C-G is described in ClinVar as Benign. ClinVar VariationId is 256339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0742 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.898+42G>C		intron	N/A	NP_000503.1
	GALNS	NM_001323544.2		c.916+42G>C		intron	N/A	NP_001310473.1
	GALNS	NM_001323543.2		c.343+42G>C		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.898+42G>C		intron	N/A	ENSP00000268695.5
	GALNS	ENST00000562593.5	TSL:1	n.4307+42G>C		intron	N/A
	GALNS	ENST00000562931.5	TSL:5	n.486+42G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0517 AC: 7861 AN: 152150 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0500

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0606

Gnomad OTH AF: 0.0603

GnomAD2 exomes AF: 0.0543 AC: 8768 AN: 161518 AF XY: 0.0576

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000335

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.0615

Gnomad OTH exome AF: 0.0638

GnomAD4 exome AF: 0.0563 AC: 78932 AN: 1401886 Hom.: 2618 Cov.: 32 AF XY: 0.0578 AC XY: 40013 AN XY: 691764

African (AFR) AF: 0.0442 AC: 1409 AN: 31870

American (AMR) AF: 0.0416 AC: 1497 AN: 35952

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3157 AN: 25212

East Asian (EAS) AF: 0.0000828 AC: 3 AN: 36216

South Asian (SAS) AF: 0.0819 AC: 6519 AN: 79588

European-Finnish (FIN) AF: 0.0231 AC: 1142 AN: 49342

Middle Eastern (MID) AF: 0.110 AC: 627 AN: 5688

European-Non Finnish (NFE) AF: 0.0567 AC: 61258 AN: 1079868

Other (OTH) AF: 0.0571 AC: 3320 AN: 58150

GnomAD4 genome AF: 0.0516 AC: 7862 AN: 152268 Hom.: 271 Cov.: 32 AF XY: 0.0505 AC XY: 3759 AN XY: 74442

African (AFR) AF: 0.0416 AC: 1728 AN: 41540

American (AMR) AF: 0.0499 AC: 764 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.0808 AC: 390 AN: 4826

European-Finnish (FIN) AF: 0.0227 AC: 241 AN: 10612

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.0606 AC: 4120 AN: 68012

Other (OTH) AF: 0.0597 AC: 126 AN: 2112

Alfa AF: 0.0622 Hom.: 63

Bravo AF: 0.0522

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.45
PhyloP100		-1.3
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: rs76095307; hg19: chr16-88901579;