chr16-88818027-C-T

Variant names:

• chr16-88818027-C-T
• rs78127134
• NM_000512.5:c.1462G>A

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_001323544.2(GALNS):​c.1480G>A​(p.Val494Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,583,156 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V494V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (36 hom.)
• Consequence: GALNS NM_001323544.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.45
• Publications: 13 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 -18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001323544.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.009323835).
• BP6: Variant 16-88818027-C-T is Benign according to our data. Variant chr16-88818027-C-T is described in ClinVar as Benign. ClinVar VariationId is 194178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00204 (311/152326) while in subpopulation EAS AF = 0.0521 (270/5180). AF 95% confidence interval is 0.047. There are 9 homozygotes in GnomAd4. There are 182 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_001323544.2. 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.1462G>A	p.Val488Met	missense	Exon 13 of 14	NP_000503.1
	GALNS	NM_001323544.2		c.1480G>A	p.Val494Met	missense	Exon 14 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.907G>A	p.Val303Met	missense	Exon 12 of 13	NP_001310472.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.1462G>A	p.Val488Met	missense	Exon 13 of 14	ENSP00000268695.5
	GALNS	ENST00000562593.5	TSL:1	n.4871G>A		non_coding_transcript_exon	Exon 11 of 12
	GALNS	ENST00000862787.1		c.1573G>A	p.Val525Met	missense	Exon 14 of 15	ENSP00000532846.1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152208 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00433 AC: 880 AN: 203200 AF XY: 0.00420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000654

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0520

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000109

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00109 AC: 1561 AN: 1430830 Hom.: 36 Cov.: 31 AF XY: 0.00115 AC XY: 814 AN XY: 710208

African (AFR) AF: 0.0000911 AC: 3 AN: 32944

American (AMR) AF: 0.0000721 AC: 3 AN: 41610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.0269 AC: 1025 AN: 38100

South Asian (SAS) AF: 0.00305 AC: 251 AN: 82378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43092

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5750

European-Non Finnish (NFE) AF: 0.0000345 AC: 38 AN: 1101856

Other (OTH) AF: 0.00402 AC: 239 AN: 59442

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152326 Hom.: 9 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.000392 AC: 6 AN: 15300

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

East Asian (EAS) AF: 0.0521 AC: 270 AN: 5180

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00291 Hom.: 5

Bravo AF: 0.00196

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00295 AC: 354

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.25
Sift	Benign	0.34	T
Sift4G	Benign	0.44	T
Polyphen		0.050	B
Vest4		0.69
MVP		0.95
MPC		0.10
ClinPred		0.016	T
GERP RS		3.1
Varity_R		0.078
gMVP		0.41
Mutation Taster		=80/20	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: rs78127134; hg19: chr16-88884435;