9-98808001-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_024642.5(GALNT12):c.303C>G(p.His101Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,548,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. H101Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

GALNT12
NM_024642.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.18

Publications

2 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3692786).

BP6

Variant 9-98808001-C-G is Benign according to our data. Variant chr9-98808001-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410580.

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT12	NM_024642.5 link	c.303C>G	p.His101Gln	missense_variant	Exon 1 of 10	ENST00000375011.4	NP_078918.3	Q8IXK2-1
GALNT12	XM_006717287.1 link	c.-726C>G		upstream_gene_variant			XP_006717350.1	Q8IXK2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNT12	ENST00000375011.4 link	c.303C>G	p.His101Gln	missense_variant	Exon 1 of 10	1	NM_024642.5	ENSP00000364150.3		Q8IXK2-1
GALNT12	ENST00000610463.1 link	n.-4C>G		upstream_gene_variant		4		ENSP00000477657.1		A0A087WT76

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000150

AC:

AN:

153366

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000232

AC:

324

AN:

1396608

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

147

AN XY:

690094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32230

American (AMR)

AF:

0.00

AC:

AN:

36696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25100

East Asian (EAS)

AF:

0.0000271

AC:

AN:

36894

South Asian (SAS)

AF:

0.00

AC:

AN:

78822

European-Finnish (FIN)

AF:

0.0000474

AC:

AN:

42170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4172

European-Non Finnish (NFE)

AF:

0.000293

AC:

317

AN:

1082564

Other (OTH)

AF:

0.0000690

AC:

AN:

57960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

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:

0.000191

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000318

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000476

AC:

ExAC

AF:

0.000175

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 101 of the GALNT12 protein (p.His101Gln). This variant is present in population databases (rs201926457, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with colorectal cancer (PMID: 29749045, 33193653). ClinVar contains an entry for this variant (Variation ID: 410580). 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: 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. -

Nov 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GALNT12-related disorder

Uncertain:1

Mar 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GALNT12 c.303C>G variant is predicted to result in the amino acid substitution p.His101Gln. This variant was reported in two colorectal cancer cohort studies (Evans et al. 2018. PubMed ID: 29749045; Djursby et al. 2020. PubMed ID: 33193653). The p.His101Gln change was reported to result in reduced enzyme activity in an in vitro assay (Evans et al. 2018. PubMed ID: 29749045). This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-101570283-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Jun 24, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.1

PhyloP100

1.2

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.34

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.016

Polyphen

0.99

Vest4

0.51

MutPred

0.58

Gain of disorder (P = 0.0532);

MVP

0.77

MPC

0.63

ClinPred

0.38

GERP RS

3.9

PromoterAI

0.0037

Neutral

(source)

Varity_R

0.54

gMVP

0.73

Mutation Taster

=32/68

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over