rs149726976

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_024642.5(GALNT12):c.889C>T(p.Arg297Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,613,962 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

GALNT12
NM_024642.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 1.64

Publications

14 publications found

Variant links:

Genes affected

GALNT12 (HGNC:19877): (polypeptide N-acetylgalactosaminyltransferase 12) This gene encodes a member of a family of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases, which catalyze the transfer of N-acetylgalactosamine (GalNAc) from UDP-GalNAc to a serine or threonine residue on a polypeptide acceptor in the initial step of O-linked protein glycosylation. Mutations in this gene are associated with an increased susceptibility to colorectal cancer.[provided by RefSeq, Mar 2011]

GALNT12 Gene-Disease associations (from GenCC):

colorectal cancer, susceptibility to, 1
Inheritance: AD Classification: LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

GALNT12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 67 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024642.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNT12	NM_024642.5	MANE Select	c.889C>T	p.Arg297Trp	missense	Exon 4 of 10	NP_078918.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNT12	ENST00000375011.4	TSL:1 MANE Select	c.889C>T	p.Arg297Trp	missense	Exon 4 of 10	ENSP00000364150.3
GALNT12	ENST00000610463.1	TSL:4	n.*320C>T		non_coding_transcript_exon	Exon 3 of 4	ENSP00000477657.1
GALNT12	ENST00000610463.1	TSL:4	n.*320C>T		3_prime_UTR	Exon 3 of 4	ENSP00000477657.1

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.000382

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000267

AC:

AN:

251148

AF XY:

0.000273

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000325

AC:

475

AN:

1461760

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

253

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.000716

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000379

AC:

421

AN:

1111940

Other (OTH)

AF:

0.000298

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000440

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41544

American (AMR)

AF:

0.00190

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68024

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000377

Hom.:

Bravo

AF:

0.000646

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 297 of the GALNT12 protein (p.Arg297Trp). This variant is present in population databases (rs149726976, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with bilateral breast cancer in addition to primary colorectal cancer (PMID: 19617566, 29749045). ClinVar contains an entry for this variant (Variation ID: 241518). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GALNT12 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GALNT12 function (PMID: 19617566, 29749045). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Dec 24, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Colorectal cancer, susceptibility to, 1

Uncertain:2

Mar 29, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 31, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R297W variant (also known as c.889C>T), located in coding exon 4 of the GALNT12 gene, results from a C to T substitution at nucleotide position 889. The arginine at codon 297 is replaced by tryptophan, an amino acid with dissimilar properties. Functional assays performed in yeast indicate that this variant has reduced activity compared to wild type (Guda K et al. Proc. Natl. Acad. Sci. U.S.A. 2009 Aug;106:12921-5). In addition, structural analysis concluded that this alteration occurs between the catalytic A and catalytic B domains and decreases protein structure stability (Hussain MR et al. J. Cell. Biochem. 2014 Feb;115:313-27). However, this alteration was observed in both 1/479 colorectal cases and in 1/400 healthy controls in one study (Evans DR et al. Hum. Mutat. 2018 Aug;39(8):1092-1101). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.

GALNT12-related disorder

Uncertain:1

May 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GALNT12 c.889C>T variant is predicted to result in the amino acid substitution p.Arg297Trp. This variant was reported in a patient with colon and breast cancer (Patient X452, Guda et al. 2009. PubMed ID: 19617566) and a patient with colon cancer (Family 1543, Evans et al. 2018. PubMed ID: 29749045). However, this variant was also found in a control individual (Evans et al. 2018. PubMed ID: 29749045). Functional characterization of this variant showed that it retained only 7% of wild type activity (Guda et al. 2009. PubMed ID: 19617566) and in silico analysis predicted a reduction of protein stability (Hussain et al. 2014. PubMed ID: 24038392). This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD and in ClinVar this variant has conflicting interpretations regarding its pathogenicity, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/241518). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.071

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.51

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.4

PhyloP100

1.6

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.65

MVP

0.79

MPC

0.59

ClinPred

0.26

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.41

gMVP

0.78

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over