rs267606841

Variant names:

• chr2-165749801-A-C
• rs267606841
• NM_004482.4:c.1720T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004482.4(GALNT3):​c.1720T>G​(p.Cys574Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALNT3 NM_004482.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 10 publications found

Genes affected

GALNT3 (HGNC:4125): (polypeptide N-acetylgalactosaminyltransferase 3) This gene encodes UDP-GalNAc transferase 3, a member of the GalNAc-transferases family. This family transfers an N-acetyl galactosamine to the hydroxyl group of a serine or threonine residue in the first step of O-linked oligosaccharide biosynthesis. Individual GalNAc-transferases have distinct activities and initiation of O-glycosylation is regulated by a repertoire of GalNAc-transferases. The protein encoded by this gene is highly homologous to other family members, however the enzymes have different substrate specificities. [provided by RefSeq, Jul 2008]

GALNT3 Gene-Disease associations (from GenCC):

• tumoral calcinosis, hyperphosphatemic, familial, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• tumoral calcinosis, hyperphosphatemic, familial, 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet

ENSG00000307262 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-165749801-A-C is Pathogenic according to our data. Variant chr2-165749801-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7803.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004482.4. 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
	GALNT3	NM_004482.4	MANE Select	c.1720T>G	p.Cys574Gly	missense	Exon 10 of 11	NP_004473.2	Q14435-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNT3	ENST00000392701.8	TSL:1 MANE Select	c.1720T>G	p.Cys574Gly	missense	Exon 10 of 11	ENSP00000376465.3	Q14435-1
	GALNT3	ENST00000409882.5	TSL:1	c.934T>G	p.Cys312Gly	missense	Exon 7 of 8	ENSP00000386955.1	E7EUL0
	GALNT3	ENST00000902717.1		c.1780T>G	p.Cys594Gly	missense	Exon 10 of 11	ENSP00000572776.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Tumoral calcinosis, hyperphosphatemic, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Gain of loop (P = 0.002)
MVP		0.99
MPC		0.53
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.95
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267606841; hg19: chr2-166606311;