chr16-88835760-G-A

Variant names:

• chr16-88835760-G-A
• rs117053987
• NM_000512.5:c.723C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000512.5(GALNS):​c.723C>T​(p.Ala241Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,158 control chromosomes in the GnomAD database, including 167 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. A241A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (9 hom., cov: 33)
  • Exomes 𝑓: 0.013 (158 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.226
• Publications: 3 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=-0.74).
• BP6: Variant 16-88835760-G-A is Benign according to our data. Variant chr16-88835760-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0082 (1250/152354) while in subpopulation NFE AF = 0.0132 (898/68040). AF 95% confidence interval is 0.0125. There are 9 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.723C>T	p.Ala241Ala	synonymous	Exon 7 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.741C>T	p.Ala247Ala	synonymous	Exon 8 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.168C>T	p.Ala56Ala	synonymous	Exon 6 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.723C>T	p.Ala241Ala	synonymous	Exon 7 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4132C>T		non_coding_transcript_exon	Exon 5 of 12
	GALNS	ENST00000862787.1		c.834C>T	p.Ala278Ala	synonymous	Exon 8 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1250 AN: 152236 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00725 AC: 1822 AN: 251340 AF XY: 0.00712

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.0126 AC: 18399 AN: 1461804 Hom.: 158 Cov.: 32 AF XY: 0.0122 AC XY: 8851 AN XY: 727202

African (AFR) AF: 0.00245 AC: 82 AN: 33480

American (AMR) AF: 0.00264 AC: 118 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 121 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.00620 AC: 331 AN: 53346

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0154 AC: 17177 AN: 1112002

Other (OTH) AF: 0.00874 AC: 528 AN: 60392

GnomAD4 genome AF: 0.00820 AC: 1250 AN: 152354 Hom.: 9 Cov.: 33 AF XY: 0.00770 AC XY: 574 AN XY: 74502

African (AFR) AF: 0.00337 AC: 140 AN: 41580

American (AMR) AF: 0.00307 AC: 47 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0132 AC: 898 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.0105 Hom.: 6

Bravo AF: 0.00827

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0117

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Mucopolysaccharidosis, MPS-IV-A (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.32
DANN	Benign	0.71
PhyloP100		0.23
Mutation Taster		=98/2	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: rs117053987; hg19: chr16-88902168;