chr16-88818058-C-T

Variant names:

• chr16-88818058-C-T
• rs2303271
• NM_000512.5:c.1431G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000512.5(GALNS):​c.1431G>A​(p.Glu477Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,578,382 control chromosomes in the GnomAD database, including 113,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13200 hom., cov: 33)
  • Exomes 𝑓: 0.37 (99808 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.22
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-88818058-C-T is Benign according to our data. Variant chr16-88818058-C-T is described in ClinVar as Benign. ClinVar VariationId is 93168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 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.1431G>A	p.Glu477Glu	synonymous	Exon 13 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.1449G>A	p.Glu483Glu	synonymous	Exon 14 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.876G>A	p.Glu292Glu	synonymous	Exon 12 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.1431G>A	p.Glu477Glu	synonymous	Exon 13 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4840G>A		non_coding_transcript_exon	Exon 11 of 12
	GALNS	ENST00000862787.1		c.1542G>A	p.Glu514Glu	synonymous	Exon 14 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62462 AN: 151894 Hom.: 13182 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.441

GnomAD2 exomes AF: 0.407 AC: 81007 AN: 198980 AF XY: 0.404

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.370 AC: 527398 AN: 1426368 Hom.: 99808 Cov.: 50 AF XY: 0.371 AC XY: 262620 AN XY: 707422

African (AFR) AF: 0.477 AC: 15771 AN: 33096

American (AMR) AF: 0.415 AC: 16716 AN: 40272

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 11115 AN: 25588

East Asian (EAS) AF: 0.625 AC: 23952 AN: 38332

South Asian (SAS) AF: 0.407 AC: 33438 AN: 82064

European-Finnish (FIN) AF: 0.338 AC: 14390 AN: 42520

Middle Eastern (MID) AF: 0.511 AC: 2921 AN: 5720

European-Non Finnish (NFE) AF: 0.351 AC: 385575 AN: 1099462

Other (OTH) AF: 0.397 AC: 23520 AN: 59314

GnomAD4 genome AF: 0.411 AC: 62521 AN: 152014 Hom.: 13200 Cov.: 33 AF XY: 0.412 AC XY: 30590 AN XY: 74294

African (AFR) AF: 0.468 AC: 19404 AN: 41438

American (AMR) AF: 0.410 AC: 6269 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3270 AN: 5170

South Asian (SAS) AF: 0.417 AC: 2010 AN: 4824

European-Finnish (FIN) AF: 0.342 AC: 3618 AN: 10566

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24889 AN: 67954

Other (OTH) AF: 0.440 AC: 929 AN: 2112

Alfa AF: 0.385 Hom.: 3812

Bravo AF: 0.421

Asia WGS AF: 0.478 AC: 1665 AN: 3478

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
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.97
DANN	Benign	0.47
PhyloP100		-1.2
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: rs2303271; hg19: chr16-88884466; COSMIC: COSV51935908;