rs11076716

Variant names:

• chr16-88814557-C-G
• rs11076716
• NM_000512.5:c.1483-32G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-88814557-C-G
• chr16-88814557-C-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.1483-32G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,549,980 control chromosomes in the GnomAD database, including 43,264 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 0.20 (3820 hom., cov: 33)
  • Exomes 𝑓: 0.23 (39444 hom.)
• Consequence: GALNS NM_000512.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.86
• Publications: 9 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 2 / 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=-0.82).
• BP6: Variant 16-88814557-C-G is Benign according to our data. Variant chr16-88814557-C-G is described in ClinVar as Benign. ClinVar VariationId is 256332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.1483-32G>C		intron_variant	Intron 13 of 13	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.1483-32G>C		intron_variant	Intron 13 of 13	1	NM_000512.5	ENSP00000268695.5
GALNS	ENST00000562593.5	n.4892-32G>C		intron_variant	Intron 11 of 11	1
GALNS	ENST00000567525.5	n.*954-32G>C		intron_variant	Intron 11 of 11	2		ENSP00000454484.1
GALNS	ENST00000568613.5	n.*1446-32G>C		intron_variant	Intron 14 of 14	2		ENSP00000457921.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31150 AN: 152102 Hom.: 3821 Cov.: 33

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.250 AC: 38637 AN: 154460 AF XY: 0.248

Gnomad AFR exome AF: 0.0832

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.259

GnomAD4 exome AF: 0.231 AC: 322352 AN: 1397760 Hom.: 39444 Cov.: 34 AF XY: 0.231 AC XY: 158959 AN XY: 689398

African (AFR) AF: 0.0842 AC: 2661 AN: 31604

American (AMR) AF: 0.272 AC: 9729 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6306 AN: 25176

East Asian (EAS) AF: 0.536 AC: 19191 AN: 35772

South Asian (SAS) AF: 0.203 AC: 16040 AN: 79202

European-Finnish (FIN) AF: 0.255 AC: 12306 AN: 48338

Middle Eastern (MID) AF: 0.302 AC: 1581 AN: 5232

European-Non Finnish (NFE) AF: 0.223 AC: 240369 AN: 1078786

Other (OTH) AF: 0.245 AC: 14169 AN: 57934

GnomAD4 genome AF: 0.205 AC: 31152 AN: 152220 Hom.: 3820 Cov.: 33 AF XY: 0.207 AC XY: 15439 AN XY: 74406

African (AFR) AF: 0.0866 AC: 3601 AN: 41562

American (AMR) AF: 0.236 AC: 3610 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 855 AN: 3472

East Asian (EAS) AF: 0.530 AC: 2742 AN: 5172

South Asian (SAS) AF: 0.207 AC: 1002 AN: 4830

European-Finnish (FIN) AF: 0.252 AC: 2665 AN: 10588

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15736 AN: 67996

Other (OTH) AF: 0.251 AC: 530 AN: 2114

Alfa AF: 0.224 Hom.: 755

Bravo AF: 0.204

Asia WGS AF: 0.312 AC: 1085 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-IV-A Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.19
DANN	Benign	0.58
PhyloP100		-2.9
BranchPoint Hunter		2.0
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: rs11076716; hg19: chr16-88880965; COSMIC: COSV51937196; COSMIC: COSV51937196;