12-85979381-T-C

Position:

• chr12-85979381-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001351288.2(MGAT4C):​c.1345A>G​(p.Ile449Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,612,352 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: MGAT4C NM_001351288.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.46

Genes affected

MGAT4C (HGNC:30871): (MGAT4 family member C) Predicted to enable acetylglucosaminyltransferase activity. Predicted to be involved in protein N-linked glycosylation. Predicted to be located in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050908923).
• BP6: Variant 12-85979381-T-C is Benign according to our data. Variant chr12-85979381-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2356291.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGAT4C	NM_001351288.2	c.1345A>G	p.Ile449Val	missense_variant	5/5	ENST00000611864.5	NP_001338217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGAT4C	ENST00000611864.5	c.1345A>G	p.Ile449Val	missense_variant	5/5	5	NM_001351288.2	ENSP00000481096	P1

Frequencies

GnomAD3 genomes AF: 0.000922 AC: 140 AN: 151904 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00135 AC: 337 AN: 250440 Hom.: 3 AF XY: 0.00138 AC XY: 187 AN XY: 135412

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00118 AC: 1719 AN: 1460330 Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 870 AN XY: 726542

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000690

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.000921 AC: 140 AN: 152022 Hom.: 1 Cov.: 32 AF XY: 0.000915 AC XY: 68 AN XY: 74350

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00102

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.1345A>G (p.I449V) alteration is located in exon 7 (coding exon 3) of the MGAT4C gene. This alteration results from a A to G substitution at nucleotide position 1345, causing the isoleucine (I) at amino acid position 449 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

MGAT4C: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.5
DANN	Benign	0.42
DEOGEN2	Benign	0.092	T;T;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.010	N;N;N;N;N
MutationTaster	Benign	0.94	D;D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.050	.;.;N;.;N
REVEL	Benign	0.035
Sift	Benign	0.55	.;.;T;.;T
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.081
MVP		0.15
ClinPred		0.010	T
GERP RS		2.3
Varity_R		0.030
gMVP		0.16

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: rs144502445; hg19: chr12-86373159;