2-165748856-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004482.4(GALNT3):c.1827T>C(p.Asn609=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00952 in 1,611,598 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (88 hom.)
• Consequence: GALNT3 NM_004482.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-165748856-A-G is Benign according to our data. Variant chr2-165748856-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 773430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00757 (1153/152214) while in subpopulation NFE AF= 0.0124 (844/67966). AF 95% confidence interval is 0.0117. There are 9 homozygotes in gnomad4. There are 524 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNT3	NM_004482.4	c.1827T>C	p.Asn609=	synonymous_variant	11/11	ENST00000392701.8
GALNT3	XM_005246449.2	c.1827T>C	p.Asn609=	synonymous_variant	11/11
GALNT3	XM_011510929.2	c.1827T>C	p.Asn609=	synonymous_variant	11/11
GALNT3	XM_017003770.2	c.1827T>C	p.Asn609=	synonymous_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNT3	ENST00000392701.8	c.1827T>C	p.Asn609=	synonymous_variant	11/11	1	NM_004482.4	P1
GALNT3	ENST00000409882.5	c.1041T>C	p.Asn347=	synonymous_variant	8/8	1

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 1153 AN: 152096 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00797 AC: 1973 AN: 247604 Hom.: 13 AF XY: 0.00804 AC XY: 1077 AN XY: 134006

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00540

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00243

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00972 AC: 14186 AN: 1459384 Hom.: 88 Cov.: 30 AF XY: 0.00958 AC XY: 6952 AN XY: 726012

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00609

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00281

Gnomad4 FIN exome AF: 0.00272

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.00757 AC: 1153 AN: 152214 Hom.: 9 Cov.: 33 AF XY: 0.00704 AC XY: 524 AN XY: 74416

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.0104 Hom.: 5

Bravo AF: 0.00770

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.0134

EpiControl AF: 0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2021	- -

Tumoral calcinosis, hyperphosphatemic, familial, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

GALNT3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	7.3
Dann	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs142136047; hg19: chr2-166605366; COSMIC: COSV101205033;