rs776700061

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The ENST00000375011.4(GALNT12):​c.1208G>A​(p.Arg403His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,994 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. R403C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

GALNT12
ENST00000375011.4 missense

Scores

6
9
4

Clinical Significance

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

Conservation

PhyloP100: 9.76
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.847
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GALNT12NM_024642.5 linkuse as main transcriptc.1208G>A p.Arg403His missense_variant 6/10 ENST00000375011.4 NP_078918.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GALNT12ENST00000375011.4 linkuse as main transcriptc.1208G>A p.Arg403His missense_variant 6/101 NM_024642.5 ENSP00000364150 P1Q8IXK2-1
GALNT12ENST00000615204.1 linkuse as main transcriptn.70G>A non_coding_transcript_exon_variant 1/33

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
251120
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135750
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000529
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000144
AC:
210
AN:
1461854
Hom.:
0
Cov.:
32
AF XY:
0.000142
AC XY:
103
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000156
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000793
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 403 of the GALNT12 protein (p.Arg403His). This variant is present in population databases (rs776700061, gnomAD 0.01%). 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: 410583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GALNT12 protein function with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 09, 2022To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00013 (4/30616 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 29, 2022The p.R403H variant (also known as c.1208G>A), located in coding exon 6 of the GALNT12 gene, results from a G to A substitution at nucleotide position 1208. The arginine at codon 403 is replaced by histidine, an amino acid with highly similar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Colorectal cancer, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 11, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.18
T
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.85
D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.9
D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.85
MVP
0.90
MPC
0.70
ClinPred
0.75
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.39
gMVP
0.72

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776700061; hg19: chr9-101599426; COSMIC: COSV66662346; COSMIC: COSV66662346; API