rs267606841

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• tumoral calcinosis, hyperphosphatemic, familial, 1

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

ENSG00000307262 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a disulfide_bond (size 13) in uniprot entity GALT3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004482.4
• 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 CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165749801-A-C is described in CliVar as Pathogenic. Clinvar id is 7803.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT3	NM_004482.4	c.1720T>G	p.Cys574Gly	missense_variant	Exon 10 of 11	ENST00000392701.8	NP_004473.2
GALNT3	XM_005246449.2	c.1720T>G	p.Cys574Gly	missense_variant	Exon 10 of 11		XP_005246506.1
GALNT3	XM_011510929.2	c.1720T>G	p.Cys574Gly	missense_variant	Exon 10 of 11		XP_011509231.1
GALNT3	XM_017003770.2	c.1720T>G	p.Cys574Gly	missense_variant	Exon 10 of 11		XP_016859259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNT3	ENST00000392701.8	c.1720T>G	p.Cys574Gly	missense_variant	Exon 10 of 11	1	NM_004482.4	ENSP00000376465.3
GALNT3	ENST00000409882.5	c.934T>G	p.Cys312Gly	missense_variant	Exon 7 of 8	1		ENSP00000386955.1
GALNT3	ENST00000715282.1	c.1720T>G	p.Cys574Gly	missense_variant	Exon 10 of 11			ENSP00000520447.1
ENSG00000307262	ENST00000824811.1	n.135A>C		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Tumoral calcinosis, hyperphosphatemic, familial, 1 Pathogenic:1

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.
PhyloP100		9.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.011	D;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;