rs151296605

Variant names:

• chr16-88818051-C-A
• rs151296605
• NM_000512.5:c.1438G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-88818051-C-A
• chr16-88818051-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000512.5(GALNS):​c.1438G>T​(p.Val480Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,582,582 control chromosomes in the GnomAD database, including 23 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. V480V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: 1.15
• 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.010627598).
• BP6: Variant 16-88818051-C-A is Benign according to our data. Variant chr16-88818051-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00554 (844/152276) while in subpopulation AFR AF = 0.0194 (808/41566). AF 95% confidence interval is 0.0183. There are 11 homozygotes in GnomAd4. There are 392 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1438G>T	p.Val480Phe	missense	Exon 13 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.1456G>T	p.Val486Phe	missense	Exon 14 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.883G>T	p.Val295Phe	missense	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.1438G>T	p.Val480Phe	missense	Exon 13 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.4847G>T		non_coding_transcript_exon	Exon 11 of 12
	GALNS	ENST00000862787.1		c.1549G>T	p.Val517Phe	missense	Exon 14 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 841 AN: 152158 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00134 AC: 270 AN: 201578 AF XY: 0.000924

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000875

Gnomad OTH exome AF: 0.000383

GnomAD4 exome AF: 0.000640 AC: 916 AN: 1430306 Hom.: 12 Cov.: 31 AF XY: 0.000562 AC XY: 399 AN XY: 709730

African (AFR) AF: 0.0208 AC: 687 AN: 33098

American (AMR) AF: 0.00178 AC: 73 AN: 40910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.00 AC: 0 AN: 38394

South Asian (SAS) AF: 0.0000972 AC: 8 AN: 82338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43380

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5738

European-Non Finnish (NFE) AF: 0.0000200 AC: 22 AN: 1101378

Other (OTH) AF: 0.00198 AC: 118 AN: 59456

GnomAD4 genome AF: 0.00554 AC: 844 AN: 152276 Hom.: 11 Cov.: 33 AF XY: 0.00527 AC XY: 392 AN XY: 74444

African (AFR) AF: 0.0194 AC: 808 AN: 41566

American (AMR) AF: 0.00150 AC: 23 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

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

Alfa AF: 0.000867 Hom.: 2

Bravo AF: 0.00618

ESP6500AA AF: 0.0175 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00154 AC: 185

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Mucopolysaccharidosis, MPS-IV-A (6)
-	1	4	not provided (5)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.017
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.32
Sift	Benign	0.032	D
Sift4G	Uncertain	0.044	D
Polyphen		0.91	P
Vest4		0.84
MVP		1.0
MPC		0.26
ClinPred		0.056	T
GERP RS		0.93
Varity_R		0.27
gMVP		0.73
Mutation Taster		=90/10	polymorphism

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: rs151296605; hg19: chr16-88884459; COSMIC: COSV106087714;