Genetic Variant GALNT12:p.Asp303His (chr9-98831947-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024642.5(GALNT12):c.907G>C(p.Asp303His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D303N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GALNT12
NM_024642.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.92

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT12	NM_024642.5 link	c.907G>C	p.Asp303His	missense_variant	Exon 4 of 10	ENST00000375011.4	NP_078918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GALNT12	ENST00000375011.4 link	c.907G>C	p.Asp303His	missense_variant	Exon 4 of 10	1	NM_024642.5	ENSP00000364150.3
GALNT12	ENST00000610463.1 link	n.*338G>C		non_coding_transcript_exon_variant	Exon 3 of 4	4		ENSP00000477657.1
GALNT12	ENST00000610463.1 link	n.*338G>C		3_prime_UTR_variant	Exon 3 of 4	4		ENSP00000477657.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727022

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111822

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.2

PhyloP100

9.9

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.50

Sift

Uncertain

0.024

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.84

MutPred

0.48

Gain of methylation at R306 (P = 0.0843);

MVP

0.86

MPC

0.68

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.85

Mutation Taster

=28/72

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over