9-98807699-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_024642.5(GALNT12):c.1A>G(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 0.00000175 in 1,145,792 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

GALNT12
NM_024642.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.464

Publications

1 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 4 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT12	NM_024642.5 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENST00000375011.4	NP_078918.3	Q8IXK2-1
LOC124902229	XR_007061689.1 link	n.-119T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNT12	ENST00000375011.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	1	NM_024642.5	ENSP00000364150.3		Q8IXK2-1
ENSG00000285706	ENST00000647710.1 link	n.-135T>C		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000100

AC:

AN:

995228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

475612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19344

American (AMR)

AF:

0.000179

AC:

AN:

5592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9992

East Asian (EAS)

AF:

0.00

AC:

AN:

15214

South Asian (SAS)

AF:

0.00

AC:

AN:

25148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2384

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

867044

Other (OTH)

AF:

0.00

AC:

AN:

36408

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

AF:

0.00000664

AC:

AN:

150564

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73510

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41164

American (AMR)

AF:

0.00

AC:

AN:

15140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67562

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 31, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the GALNT12 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. A close match alteration, c.3G>T (p.M1?) 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. -

not provided

Uncertain:1

Dec 04, 2023

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). Disruption of the initiator codon has been observed in individual(s) with breast and colon cancer (PMID: 19617566, 36315513). ClinVar contains an entry for this variant (Variation ID: 1403848). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GALNT12 function (PMID: 19617566). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.012

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-1.0

PhyloP100

0.46

PROVEAN

Benign

0.26

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.063

Vest4

0.73

MutPred

0.62

Loss of loop (P = 0.1258);

MVP

0.46

ClinPred

0.98

GERP RS

3.3

PromoterAI

0.030

Neutral

(source)

Varity_R

0.86

gMVP

0.53

Mutation Taster

=18/182

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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9-98807699-A-G

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