9-98826890-T-A

Position:

• chr9-98826890-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_024642.5(GALNT12):​c.680T>A​(p.Leu227Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,435,436 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: 0.000015 (0 hom.)
• Consequence: GALNT12 NM_024642.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.01

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 Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNT12	NM_024642.5	c.680T>A	p.Leu227Gln	missense_variant	3/10	ENST00000375011.4	NP_078918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNT12	ENST00000375011.4	c.680T>A	p.Leu227Gln	missense_variant	3/10	1	NM_024642.5	ENSP00000364150.3
GALNT12	ENST00000610463.1	n.*111T>A		non_coding_transcript_exon_variant	2/4	4		ENSP00000477657.1
GALNT12	ENST00000610463.1	n.*111T>A		3_prime_UTR_variant	2/4	4		ENSP00000477657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000497 AC: 1 AN: 201190 Hom.: 0 AF XY: 0.00000925 AC XY: 1 AN XY: 108160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 21 AN: 1435436 Hom.: 0 Cov.: 32 AF XY: 0.0000112 AC XY: 8 AN XY: 711554

Gnomad4 AFR exome AF: 0.00

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: 0.0000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2022

The p.L227Q variant (also known as c.680T>A), located in coding exon 3 of the GALNT12 gene, results from a T to A substitution at nucleotide position 680. The leucine at codon 227 is replaced by glutamine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Colorectal cancer, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 21, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 227 of the GALNT12 protein (p.Leu227Gln). This variant is present in population databases (rs763057175, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with GALNT12-related conditions. ClinVar contains an entry for this variant (Variation ID: 410582). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALNT12 protein function. 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
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.93
MPC		0.64
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs763057175; hg19: chr9-101589172;