rs41306504

chr9-98831821-G-Achr9-98831821-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024642.5(GALNT12):c.781G>A(p.Asp261Asn) variant causes a missense change. The variant allele was found at a frequency of 0.012 in 1,614,166 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D261H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: GALNT12 NM_024642.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.84

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010009915).
• BP6: Variant 9-98831821-G-A is Benign according to our data. Variant chr9-98831821-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-98831821-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0122 (17892/1461884) while in subpopulation MID AF= 0.0194 (112/5768). AF 95% confidence interval is 0.0165. There are 152 homozygotes in gnomad4_exome. There are 9125 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1546 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNT12	NM_024642.5	c.781G>A	p.Asp261Asn	missense_variant	4/10	ENST00000375011.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNT12	ENST00000375011.4	c.781G>A	p.Asp261Asn	missense_variant	4/10	1	NM_024642.5	P1
GALNT12	ENST00000610463.1	c.*212G>A		3_prime_UTR_variant, NMD_transcript_variant	3/4	4

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1546 AN: 152164 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0119 AC: 2988 AN: 251464 Hom.: 22 AF XY: 0.0125 AC XY: 1703 AN XY: 135902

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00925

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0122 AC: 17892 AN: 1461884 Hom.: 152 Cov.: 32 AF XY: 0.0125 AC XY: 9125 AN XY: 727242

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00953

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0102 AC: 1547 AN: 152282 Hom.: 12 Cov.: 32 AF XY: 0.0103 AC XY: 769 AN XY: 74464

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0111 Hom.: 18

Bravo AF: 0.00858

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.0114 AC: 1385

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 26, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.34
Sift	Benign	0.060	T
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.25
MPC		0.60
ClinPred		0.0091	T
GERP RS		5.7
Varity_R		0.70
gMVP		0.71

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: rs41306504; hg19: chr9-101594103; COSMIC: COSV66662367;