9-98807701-G-T

Variant names:

• chr9-98807701-G-T
• rs267606839
• NM_024642.5:c.3G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_024642.5(GALNT12):​c.3G>T​(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 0.000012 in 999,742 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: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GALNT12 NM_024642.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.59
• Publications: 1 publications found

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)

ENSG00000285706 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 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.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT12	NM_024642.5	c.3G>T	p.Met1?	start_lost	Exon 1 of 10	ENST00000375011.4	NP_078918.3
LOC124902229	XR_007061689.1	n.-121C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNT12	ENST00000375011.4	c.3G>T	p.Met1?	start_lost	Exon 1 of 10	1	NM_024642.5	ENSP00000364150.3
ENSG00000285706	ENST00000647710.1	n.-137C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000120 AC: 12 AN: 999742 Hom.: 0 Cov.: 30 AF XY: 0.0000105 AC XY: 5 AN XY: 478318

African (AFR) AF: 0.00 AC: 0 AN: 19444

American (AMR) AF: 0.00 AC: 0 AN: 5906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10218

East Asian (EAS) AF: 0.00 AC: 0 AN: 15418

South Asian (SAS) AF: 0.000275 AC: 7 AN: 25482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2420

European-Non Finnish (NFE) AF: 0.00000345 AC: 3 AN: 869878

Other (OTH) AF: 0.0000546 AC: 2 AN: 36644

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000872 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.3G>T) is located in coding exon 1 of the GALNT12 gene and results from a G to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG).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 evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

not provided Uncertain:1

Feb 26, 2024

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/or colon cancer (PMID: 19617566, 36315513). ClinVar contains an entry for this variant (Variation ID: 639336). Studies have shown that disruption of the initiator codon alters GALNT12 gene expression (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	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.97	T
PhyloP100		2.6
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
PromoterAI		-0.11	Neutral
Varity_R		0.88
gMVP		0.49
Mutation Taster		=36/164	disease causing

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

Other links and lift over

dbSNP: rs267606839; hg19: chr9-101569983;