8-19405784-GTT-GT

Variant names:

• chr8-19405784-GT-G
• rs778908076
• NM_001354483.2:c.1594delA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001354483.2(CSGALNACT1):​c.1594delA​(p.Thr532HisfsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CSGALNACT1 NM_001354483.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.981
• Publications: 0 publications found

Genes affected

CSGALNACT1 (HGNC:24290): (chondroitin sulfate N-acetylgalactosaminyltransferase 1) This gene encodes an enzyme that transfers N-acetylglucosamine (GalNAc) to the core tetrasaccharide linker and to elongating chondroitin sulfate chains in proteoglycans. Knockout of the orthologous mouse gene indicates that the protein is necessary for normal cartilage development and aggrecan metabolism. Mutations in this gene are associated with multiple sclerosis progression, and with mild skeletal dysplasia and joint laxity. [provided by RefSeq, Aug 2017]

CSGALNACT1 Gene-Disease associations (from GenCC):

• skeletal dysplasia, mild, with joint laxity and advanced bone age

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00313 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354483.2. 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
	CSGALNACT1	NM_001354483.2	MANE Select	c.1594delA	p.Thr532HisfsTer43	frameshift	Exon 9 of 9	NP_001341412.1	Q8TDX6-1
	CSGALNACT1	NM_001130518.2		c.1594delA	p.Thr532HisfsTer43	frameshift	Exon 10 of 10	NP_001123990.1	Q8TDX6-1
	CSGALNACT1	NM_001354475.2		c.1594delA	p.Thr532HisfsTer43	frameshift	Exon 10 of 10	NP_001341404.1	Q8TDX6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSGALNACT1	ENST00000692225.2	MANE Select	c.1594delA	p.Thr532HisfsTer43	frameshift	Exon 9 of 9	ENSP00000509853.1	Q8TDX6-1
	CSGALNACT1	ENST00000332246.10	TSL:1	c.1594delA	p.Thr532HisfsTer43	frameshift	Exon 10 of 10	ENSP00000330805.6	Q8TDX6-1
	CSGALNACT1	ENST00000454498.6	TSL:1	c.1594delA	p.Thr532HisfsTer43	frameshift	Exon 10 of 10	ENSP00000411816.2	Q8TDX6-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251358 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98

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: rs778908076; hg19: chr8-19263295; COSMIC: COSV59974633;