16-88836179-A-G

Variant names:

• chr16-88836179-A-G
• rs201579340
• NM_000512.5:c.633+22T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000512.5(GALNS):​c.633+22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,609,932 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (18 hom.)
• Consequence: GALNS NM_000512.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.293
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-88836179-A-G is Benign according to our data. Variant chr16-88836179-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 256334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.633+22T>C		intron	N/A	NP_000503.1
	GALNS	NM_001323544.2		c.651+22T>C		intron	N/A	NP_001310473.1
	GALNS	NM_001323543.2		c.78+22T>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.633+22T>C		intron	N/A	ENSP00000268695.5
	GALNS	ENST00000562593.5	TSL:1	n.4042+22T>C		intron	N/A
	GALNS	ENST00000562831.1	TSL:3	c.417+22T>C		intron	N/A	ENSP00000455174.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152164 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00143 AC: 358 AN: 249804 AF XY: 0.00195

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000949

Gnomad NFE exome AF: 0.000478

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000860 AC: 1253 AN: 1457650 Hom.: 18 Cov.: 31 AF XY: 0.00113 AC XY: 817 AN XY: 725394

African (AFR) AF: 0.0000599 AC: 2 AN: 33362

American (AMR) AF: 0.000426 AC: 19 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00879 AC: 757 AN: 86096

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 52866

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5762

European-Non Finnish (NFE) AF: 0.000361 AC: 400 AN: 1108880

Other (OTH) AF: 0.000797 AC: 48 AN: 60254

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152282 Hom.: 2 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74470

African (AFR) AF: 0.0000481 AC: 2 AN: 41572

American (AMR) AF: 0.00177 AC: 27 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67998

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000499

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 31, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.5
DANN	Benign	0.34
PhyloP100		-0.29
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: rs201579340; hg19: chr16-88902587;