9-98826901-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_024642.5(GALNT12):c.691T>C(p.Cys231Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000272 in 1,581,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C231Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GALNT12
NM_024642.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.01

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT12	NM_024642.5 link	c.691T>C	p.Cys231Arg	missense_variant	Exon 3 of 10	ENST00000375011.4	NP_078918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GALNT12	ENST00000375011.4 link	c.691T>C	p.Cys231Arg	missense_variant	Exon 3 of 10	1	NM_024642.5	ENSP00000364150.3
GALNT12	ENST00000610463.1 link	n.*122T>C		non_coding_transcript_exon_variant	Exon 2 of 4	4		ENSP00000477657.1
GALNT12	ENST00000610463.1 link	n.*122T>C		3_prime_UTR_variant	Exon 2 of 4	4		ENSP00000477657.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000259

AC:

AN:

193186

AF XY:

0.0000289

show subpopulations

Gnomad AFR exome

AF:

0.0000876

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:

0.0000485

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000259

AC:

AN:

1429600

Hom.:

Cov.:

AF XY:

0.0000254

AC XY:

AN XY:

708180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32816

American (AMR)

AF:

0.00

AC:

AN:

39734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25484

East Asian (EAS)

AF:

0.0000263

AC:

AN:

38080

South Asian (SAS)

AF:

0.00

AC:

AN:

81922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.0000310

AC:

AN:

1095926

Other (OTH)

AF:

0.0000338

AC:

AN:

59172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.0000283

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C231R variant (also known as c.691T>C), located in coding exon 3 of the GALNT12 gene, results from a T to C substitution at nucleotide position 691. The cysteine at codon 231 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Colorectal cancer, susceptibility to, 1

Uncertain:1

Jan 22, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 231 of the GALNT12 protein (p.Cys231Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GALNT12-related conditions. ClinVar contains an entry for this variant (Variation ID: 410592). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALNT12 protein function. 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. -

GALNT12-related disorder

Uncertain:1

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GALNT12 c.691T>C variant is predicted to result in the amino acid substitution p.Cys231Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0051% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and it is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/410592/). 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

4.1

PhyloP100

8.0

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.99

MutPred

0.74

Loss of helix (P = 0.3949);

MVP

0.94

MPC

0.85

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

1.0

gMVP

0.92

Mutation Taster

=6/94

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