16-88835336-G-T

Variant names:

• chr16-88835336-G-T
• rs61742258
• NM_000512.5:c.775C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000512.5(GALNS):​c.775C>A​(p.Arg259Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00418 in 1,613,664 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R259R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (25 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.90
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 16-88835336-G-T is Benign according to our data. Variant chr16-88835336-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 288253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 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.775C>A	p.Arg259Arg	synonymous	Exon 8 of 14	NP_000503.1
	GALNS	NM_001323544.2		c.793C>A	p.Arg265Arg	synonymous	Exon 9 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.220C>A	p.Arg74Arg	synonymous	Exon 7 of 13	NP_001310472.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.775C>A	p.Arg259Arg	synonymous	Exon 8 of 14	ENSP00000268695.5
	GALNS	ENST00000562593.5	TSL:1	n.4184C>A		non_coding_transcript_exon	Exon 6 of 12
	GALNS	ENST00000562931.5	TSL:5	n.363C>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 667 AN: 152156 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00451 AC: 1128 AN: 250168 AF XY: 0.00460

Gnomad AFR exome AF: 0.000874

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00609

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00620

Gnomad NFE exome AF: 0.00654

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00416 AC: 6080 AN: 1461390 Hom.: 25 Cov.: 33 AF XY: 0.00434 AC XY: 3152 AN XY: 726906

African (AFR) AF: 0.000777 AC: 26 AN: 33468

American (AMR) AF: 0.00305 AC: 136 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 164 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86074

European-Finnish (FIN) AF: 0.00570 AC: 304 AN: 53364

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.00453 AC: 5034 AN: 1111846

Other (OTH) AF: 0.00402 AC: 243 AN: 60392

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152274 Hom.: 6 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74446

African (AFR) AF: 0.000602 AC: 25 AN: 41550

American (AMR) AF: 0.00366 AC: 56 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4816

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00710 AC: 483 AN: 68020

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00471 Hom.: 2

Bravo AF: 0.00361

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00534

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Mucopolysaccharidosis, MPS-IV-A (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.9
DANN	Benign	0.69
PhyloP100		3.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61742258; hg19: chr16-88901744;