chr2-165748797-A-C

Variant names:

• chr2-165748797-A-C
• rs755865415
• NM_004482.4:c.1886T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004482.4(GALNT3):​c.1886T>G​(p.Leu629Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GALNT3 NM_004482.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.31
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32313335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT3	NM_004482.4	c.1886T>G	p.Leu629Arg	missense_variant	Exon 11 of 11	ENST00000392701.8	NP_004473.2
GALNT3	XM_005246449.2	c.1886T>G	p.Leu629Arg	missense_variant	Exon 11 of 11		XP_005246506.1
GALNT3	XM_011510929.2	c.1886T>G	p.Leu629Arg	missense_variant	Exon 11 of 11		XP_011509231.1
GALNT3	XM_017003770.2	c.1886T>G	p.Leu629Arg	missense_variant	Exon 11 of 11		XP_016859259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNT3	ENST00000392701.8	c.1886T>G	p.Leu629Arg	missense_variant	Exon 11 of 11	1	NM_004482.4	ENSP00000376465.3
GALNT3	ENST00000409882.5	c.1100T>G	p.Leu367Arg	missense_variant	Exon 8 of 8	1		ENSP00000386955.1
GALNT3	ENST00000715282.1	c.1886T>G	p.Leu629Arg	missense_variant	Exon 11 of 11			ENSP00000520447.1
ENSG00000307262	ENST00000824811.1	n.131-1000A>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248716 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 6.85e-7 AC: 1 AN: 1459026 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725808

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.0000225 AC: 1 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110400

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1886T>G (p.L629R) alteration is located in exon 11 (coding exon 10) of the GALNT3 gene. This alteration results from a T to G substitution at nucleotide position 1886, causing the leucine (L) at amino acid position 629 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.55	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		8.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.048	B;.
Vest4		0.45
MutPred		0.61		Gain of MoRF binding (P = 9e-04);.;
MVP		0.81
MPC		0.13
ClinPred		0.67	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.78
Mutation Taster		=62/38	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: rs755865415; hg19: chr2-166605307;