2-165748595-G-A

Variant names:

• chr2-165748595-G-A
• rs183674066
• NM_004482.4:c.*186C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004482.4(GALNT3):​c.*186C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 593,424 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (3 hom.)
• Consequence: GALNT3 NM_004482.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.38
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 2-165748595-G-A is Benign according to our data. Variant chr2-165748595-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 894426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00558 (848/152096) while in subpopulation AFR AF = 0.0194 (807/41518). AF 95% confidence interval is 0.0183. There are 5 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT3	NM_004482.4	c.*186C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000392701.8	NP_004473.2
GALNT3	XM_005246449.2	c.*186C>T		3_prime_UTR_variant	Exon 11 of 11		XP_005246506.1
GALNT3	XM_011510929.2	c.*186C>T		3_prime_UTR_variant	Exon 11 of 11		XP_011509231.1
GALNT3	XM_017003770.2	c.*186C>T		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.*186C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_004482.4	ENSP00000376465.3
GALNT3	ENST00000409882.5	c.*186C>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000386955.1
GALNT3	ENST00000715282.1	c.*186C>T		3_prime_UTR_variant	Exon 11 of 11			ENSP00000520447.1
ENSG00000307262	ENST00000824811.1	n.131-1202G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 845 AN: 151976 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000872 AC: 385 AN: 441328 Hom.: 3 Cov.: 5 AF XY: 0.000804 AC XY: 189 AN XY: 235106

African (AFR) AF: 0.0210 AC: 258 AN: 12280

American (AMR) AF: 0.00146 AC: 28 AN: 19200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13232

East Asian (EAS) AF: 0.00 AC: 0 AN: 29882

South Asian (SAS) AF: 0.000111 AC: 5 AN: 44884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26952

Middle Eastern (MID) AF: 0.00593 AC: 11 AN: 1854

European-Non Finnish (NFE) AF: 0.000175 AC: 47 AN: 267820

Other (OTH) AF: 0.00143 AC: 36 AN: 25224

GnomAD4 genome AF: 0.00558 AC: 848 AN: 152096 Hom.: 5 Cov.: 32 AF XY: 0.00538 AC XY: 400 AN XY: 74352

African (AFR) AF: 0.0194 AC: 807 AN: 41518

American (AMR) AF: 0.00131 AC: 20 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67948

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00506 Hom.: 0

Bravo AF: 0.00646

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

May 25, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		3.4
Mutation Taster		=99/1	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: rs183674066; hg19: chr2-166605105; COSMIC: COSV105330989;