Genetic Variant GALNT12:p.Met1? (chr9-98807699-A-T) – ACMG Classification: Uncertain_significance (4 pts)

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>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GALNT12
NM_024642.5 initiator_codon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.464

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:

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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>T	p.Met1?	initiator_codon_variant	Exon 1 of 10	ENST00000375011.4	NP_078918.3	Q8IXK2-1
LOC124902229	XR_007061689.1 link	n.-119T>A		upstream_gene_variant

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

995228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

475612

African (AFR)

AF:

0.00

AC:

AN:

19344

American (AMR)

AF:

0.00

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.1A>T), located in coding exon 1 of the GALNT12 gene, results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. 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. However, the gene-disease association for GALNT12 is limited. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.012

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-1.0

PhyloP100

0.46

PROVEAN

Benign

-0.070

REVEL

Benign

0.29

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.055

Vest4

0.78

MutPred

0.61

Loss of loop (P = 0.1258);

MVP

0.32

ClinPred

0.98

GERP RS

3.3

PromoterAI

0.046

Neutral

(source)

Varity_R

0.90

gMVP

0.49

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over