rs144553163

Positions:

• chr19-35299590-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002361.4(MAG):​c.452C>T​(p.Ala151Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,602,818 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 28)
  • Exomes 𝑓: 0.0054 (37 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.35

Genes affected

MAG (HGNC:6783): (myelin associated glycoprotein) The protein encoded by this gene is a type I membrane protein and member of the immunoglobulin superfamily. It is thought to be involved in the process of myelination. It is a lectin that binds to sialylated glycoconjugates and mediates certain myelin-neuron cell-cell interactions. Three alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009121209).
• BP6: Variant 19-35299590-C-T is Benign according to our data. Variant chr19-35299590-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00396 (602/152004) while in subpopulation NFE AF= 0.00703 (478/67970). AF 95% confidence interval is 0.00651. There are 3 homozygotes in gnomad4. There are 265 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAG	NM_002361.4	c.452C>T	p.Ala151Val	missense_variant	5/11	ENST00000392213.8
MAG	NM_001199216.2	c.377C>T	p.Ala126Val	missense_variant	5/11
MAG	NM_080600.3	c.452C>T	p.Ala151Val	missense_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAG	ENST00000392213.8	c.452C>T	p.Ala151Val	missense_variant	5/11	1	NM_002361.4	P1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 151888 Hom.: 3 Cov.: 28

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00703

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00368 AC: 899 AN: 244414 Hom.: 3 AF XY: 0.00385 AC XY: 511 AN XY: 132570

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.000609

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00443

Gnomad FIN exome AF: 0.000659

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00536

GnomAD4 exome AF: 0.00544 AC: 7893 AN: 1450814 Hom.: 37 Cov.: 31 AF XY: 0.00555 AC XY: 3990 AN XY: 719514

Gnomad4 AFR exome AF: 0.00112

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.000347

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00513

Gnomad4 FIN exome AF: 0.00102

Gnomad4 NFE exome AF: 0.00633

Gnomad4 OTH exome AF: 0.00425

GnomAD4 genome AF: 0.00396 AC: 602 AN: 152004 Hom.: 3 Cov.: 28 AF XY: 0.00357 AC XY: 265 AN XY: 74294

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00478

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00703

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00558 Hom.: 4

Bravo AF: 0.00398

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00413 AC: 501

EpiCase AF: 0.00687

EpiControl AF: 0.00689

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Mar 07, 2017

- -

Hereditary spastic paraplegia 75 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

MAG: BS1 -

MAG-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	.;T;.;.;.
Eigen	Benign	0.074
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.0091	T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	.;L;L;.;.
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	.;N;N;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.071	.;T;T;.;D
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.98	.;D;.;.;.
Vest4		0.12, 0.12, 0.11
MVP		0.65
MPC		0.48
ClinPred		0.017	T
GERP RS		4.6
Varity_R		0.22
gMVP		0.56

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: rs144553163; hg19: chr19-35790493;