9-98807701-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1 PS1_Moderate BS2

The NM_024642.5(GALNT12):c.3G>A(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 0.0000617 in 1,150,776 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 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: GALNT12 NM_024642.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 2.59

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_024642.5 (GALNT12) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1319621
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNT12	NM_024642.5	c.3G>A	p.Met1?	start_lost	1/10	ENST00000375011.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNT12	ENST00000375011.4	c.3G>A	p.Met1?	start_lost	1/10	1	NM_024642.5	P1

Frequencies

GnomAD3 genomes AF: 0.000311 AC: 47 AN: 150924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 24 AN: 999744 Hom.: 0 Cov.: 30 AF XY: 0.0000167 AC XY: 8 AN XY: 478320

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000546

GnomAD4 genome AF: 0.000311 AC: 47 AN: 151032 Hom.: 0 Cov.: 32 AF XY: 0.000244 AC XY: 18 AN XY: 73830

Gnomad4 AFR AF: 0.00109

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	This variant disrupts in the translation initiation codon of the GALNT12 mRNA and is predicted to interfere with GALNT12 protein synthesis, however, further research is needed. The frequency of this variant in the general population, 0.0011 (45/41310 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an African American female affected with colon cancer and breast cancer (PMID: 19617566 (2009)). Although the authors of this study were unable to detect any expression of the GALNT12 protein or activity after multiple attempts at transfection, the clinical and in vitro data are limited. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	This sequence change affects the initiator methionine of the GALNT12 mRNA. The next in-frame methionine is located at codon 65. This variant is present in population databases (rs267606839, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of the initiator codon has been observed in individual(s) with colon cancer and breast cancer (PMID: 19617566, 36315513). ClinVar contains an entry for this variant (Variation ID: 1270). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The p.M1? variant (also known as c.3G>A), located in coding exon 1 of the GALNT12 gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This alteration 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). This alteration is expected to modify the initiation codon (ATG) resulting 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. -

Colorectal cancer, susceptibility to, 1 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 04, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	0.22	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.12	B
Vest4		0.86
MutPred		0.65		Gain of catalytic residue at M1 (P = 0.0188);
MVP		0.52
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.88
gMVP		0.49

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

Other links and lift over

dbSNP: rs267606839; hg19: chr9-101569983;