NM_000512.5:c.708C>T

Variant names:

• chr16-88835775-G-A
• rs1064315
• NM_000512.5:c.708C>T

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.708C>T​(p.His236His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,613,812 control chromosomes in the GnomAD database, including 56,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5278 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50881 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.355
• Publications: 25 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=-0.6).
• BP6: Variant 16-88835775-G-A is Benign according to our data. Variant chr16-88835775-G-A is described in ClinVar as Benign. ClinVar VariationId is 93186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.355 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 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.708C>T	p.His236His	synonymous	Exon 7 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.726C>T	p.His242His	synonymous	Exon 8 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.153C>T	p.His51His	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.708C>T	p.His236His	synonymous	Exon 7 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4117C>T		non_coding_transcript_exon	Exon 5 of 12
	GALNS	ENST00000862787.1		c.819C>T	p.His273His	synonymous	Exon 8 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38808 AN: 152082 Hom.: 5282 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.280 AC: 70392 AN: 251306 AF XY: 0.279

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.570

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.257 AC: 376140 AN: 1461610 Hom.: 50881 Cov.: 44 AF XY: 0.258 AC XY: 187948 AN XY: 727100

African (AFR) AF: 0.211 AC: 7063 AN: 33474

American (AMR) AF: 0.287 AC: 12848 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6935 AN: 26134

East Asian (EAS) AF: 0.580 AC: 23027 AN: 39694

South Asian (SAS) AF: 0.274 AC: 23601 AN: 86252

European-Finnish (FIN) AF: 0.269 AC: 14354 AN: 53304

Middle Eastern (MID) AF: 0.334 AC: 1926 AN: 5768

European-Non Finnish (NFE) AF: 0.243 AC: 269843 AN: 1111874

Other (OTH) AF: 0.274 AC: 16543 AN: 60392

GnomAD4 genome AF: 0.255 AC: 38820 AN: 152202 Hom.: 5278 Cov.: 33 AF XY: 0.257 AC XY: 19129 AN XY: 74404

African (AFR) AF: 0.209 AC: 8695 AN: 41546

American (AMR) AF: 0.254 AC: 3886 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3470

East Asian (EAS) AF: 0.567 AC: 2931 AN: 5166

South Asian (SAS) AF: 0.276 AC: 1332 AN: 4834

European-Finnish (FIN) AF: 0.270 AC: 2857 AN: 10592

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17172 AN: 67976

Other (OTH) AF: 0.279 AC: 589 AN: 2112

Alfa AF: 0.253 Hom.: 11735

Bravo AF: 0.255

Asia WGS AF: 0.368 AC: 1282 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.262

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.052
DANN	Benign	0.58
PhyloP100		-0.35
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064315; hg19: chr16-88902183; COSMIC: COSV51935790; COSMIC: COSV51935790;