rs771919992

Variant names:

• chr2-165748638-C-T
• rs771919992
• NM_004482.4:c.*143G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004482.4(GALNT3):​c.*143G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000928 in 732,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GALNT3 NM_004482.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.988
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT3	NM_004482.4	c.*143G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000392701.8	NP_004473.2
GALNT3	XM_005246449.2	c.*143G>A		3_prime_UTR_variant	Exon 11 of 11		XP_005246506.1
GALNT3	XM_011510929.2	c.*143G>A		3_prime_UTR_variant	Exon 11 of 11		XP_011509231.1
GALNT3	XM_017003770.2	c.*143G>A		3_prime_UTR_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.*143G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_004482.4	ENSP00000376465.3
GALNT3	ENST00000409882.5	c.*143G>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000386955.1
GALNT3	ENST00000715282.1	c.*143G>A		3_prime_UTR_variant	Exon 11 of 11			ENSP00000520447.1
ENSG00000307262	ENST00000824811.1	n.131-1159C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000999 AC: 58 AN: 580836 Hom.: 0 Cov.: 8 AF XY: 0.000111 AC XY: 34 AN XY: 306624

African (AFR) AF: 0.00 AC: 0 AN: 15176

American (AMR) AF: 0.0000396 AC: 1 AN: 25250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16286

East Asian (EAS) AF: 0.00 AC: 0 AN: 31778

South Asian (SAS) AF: 0.00 AC: 0 AN: 51460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2240

European-Non Finnish (NFE) AF: 0.000148 AC: 56 AN: 377154

Other (OTH) AF: 0.0000327 AC: 1 AN: 30542

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tumoral calcinosis, hyperphosphatemic, familial, 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		0.99
Mutation Taster		=100/0	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: rs771919992; hg19: chr2-166605148;