9-98807699-A-G

Position:

• chr9-98807699-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.464

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 Pathogenic. Variant got 12 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150564 Hom.: 0 Cov.: 32

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: 1 AN: 995228 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 475612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

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: 0.00

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150564 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73510

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 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 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	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.063	B
Vest4		0.73
MutPred		0.62		Loss of loop (P = 0.1258);
MVP		0.46
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.86
gMVP		0.53

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: rs1259048855; hg19: chr9-101569981;