9-98807700-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_024642.5(GALNT12):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000402 in 995,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

GALNT12
NM_024642.5 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 0.611

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:

ENSG00000285706 (HGNC:):

ENSG00000285706 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 65 codons. Genomic position: 98807891. Lost 0.111 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-98807700-T-C is Pathogenic according to our data. Variant chr9-98807700-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1319621.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT12	NM_024642.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENST00000375011.4	NP_078918.3	Q8IXK2-1
LOC124902229	XR_007061689.1 link	n.-120A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNT12	ENST00000375011.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	1	NM_024642.5	ENSP00000364150.3		Q8IXK2-1
ENSG00000285706	ENST00000647710.1 link	n.-136A>G		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

5802

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000402

AC:

AN:

995566

Hom.:

Cov.:

AF XY:

0.00000420

AC XY:

AN XY:

476000

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19342

American (AMR)

AF:

0.00

AC:

AN:

5644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10048

East Asian (EAS)

AF:

0.00

AC:

AN:

15170

South Asian (SAS)

AF:

0.00

AC:

AN:

25264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2408

European-Non Finnish (NFE)

AF:

0.00000231

AC:

AN:

867216

Other (OTH)

AF:

0.0000549

AC:

AN:

36426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Nov 03, 2021

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the GALNT12 mRNA. The next in-frame methionine is located at codon 65. This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that disruption of the initiator codon affects GALNT12 function (PMID: 19617566). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1319621). Disruption of the initiator codon has been observed in individual(s) with breast cancer and/or colon cancer (PMID: 19617566). -

not specified

Uncertain:1

Feb 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the GALNT12 gene and results from an T to C substitution at nucleotide position 2.This alters the methionine residue at the initiation codon (ATG). A different alteration that also affects the initiation codon, c.3G>A, was reported in an African American woman with colon and breast cancer, and showed absence of protein expression in functional studies (Guda K et al. Proc. Natl. Acad. Sci. U.S.A., 2009 Aug;106:12921-5). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.012

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.92

PhyloP100

0.61

PROVEAN

Benign

-0.18

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0020

Vest4

0.47

MutPred

0.62

Gain of phosphorylation at M1 (P = 0.0063);

MVP

0.57

ClinPred

0.97

GERP RS

3.3

PromoterAI

-0.24

Neutral

(source)

Varity_R

0.77

gMVP

0.53

Mutation Taster

=32/168

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-98807700-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over