2-165747998-T-C

Variant names:

• chr2-165747998-T-C
• rs115493554
• NM_004482.4:c.*783A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004482.4(GALNT3):​c.*783A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00856 in 177,222 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0097 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: GALNT3 NM_004482.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-165747998-T-C is Benign according to our data. Variant chr2-165747998-T-C is described in ClinVar as [Benign]. Clinvar id is 331773.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00971 (1477/152140) while in subpopulation AFR AF = 0.0339 (1406/41532). AF 95% confidence interval is 0.0324. There are 23 homozygotes in GnomAd4. There are 692 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT3	NM_004482.4	c.*783A>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000392701.8	NP_004473.2
GALNT3	XM_005246449.2	c.*783A>G		3_prime_UTR_variant	Exon 11 of 11		XP_005246506.1
GALNT3	XM_011510929.2	c.*783A>G		3_prime_UTR_variant	Exon 11 of 11		XP_011509231.1
GALNT3	XM_017003770.2	c.*783A>G		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.*783A>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_004482.4	ENSP00000376465.3
GALNT3	ENST00000409882.5	c.*783A>G		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000386955.1
ENSG00000307262	ENST00000824811.1	n.130+1075T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00960 AC: 1459 AN: 152022 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00480

GnomAD4 exome AF: 0.00159 AC: 40 AN: 25082 Hom.: 1 Cov.: 0 AF XY: 0.00122 AC XY: 14 AN XY: 11480

African (AFR) AF: 0.0378 AC: 32 AN: 846

American (AMR) AF: 0.00174 AC: 1 AN: 574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1478

East Asian (EAS) AF: 0.00 AC: 0 AN: 5512

South Asian (SAS) AF: 0.00 AC: 0 AN: 206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 148

European-Non Finnish (NFE) AF: 0.0000702 AC: 1 AN: 14238

Other (OTH) AF: 0.00290 AC: 6 AN: 2068

GnomAD4 genome AF: 0.00971 AC: 1477 AN: 152140 Hom.: 23 Cov.: 32 AF XY: 0.00930 AC XY: 692 AN XY: 74374

African (AFR) AF: 0.0339 AC: 1406 AN: 41532

American (AMR) AF: 0.00380 AC: 58 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.00475 AC: 10 AN: 2104

Alfa AF: 0.00327 Hom.: 3

Bravo AF: 0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tumoral calcinosis, hyperphosphatemic, familial, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.8
DANN	Benign	0.85
PhyloP100		-1.3
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: rs115493554; hg19: chr2-166604508;