rs144553163

Variant names:

• chr19-35299590-C-T
• rs144553163
• NM_002361.4:c.452C>T

Variant summary

Our verdict is Benign. The variant received -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:2 B:3
• Conservation: PhyloP100: 2.35
• Publications: 12 publications found

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]

MAG Gene-Disease associations (from GenCC):

• complex hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 75

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 424686.
• 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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002361.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAG	NM_002361.4	MANE Select	c.452C>T	p.Ala151Val	missense	Exon 5 of 11	NP_002352.1	P20916-1
	MAG	NM_001199216.2		c.377C>T	p.Ala126Val	missense	Exon 5 of 11	NP_001186145.1	P20916-3
	MAG	NM_080600.3		c.452C>T	p.Ala151Val	missense	Exon 5 of 12	NP_542167.1	P20916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAG	ENST00000392213.8	TSL:1 MANE Select	c.452C>T	p.Ala151Val	missense	Exon 5 of 11	ENSP00000376048.2	P20916-1
	MAG	ENST00000537831.2	TSL:1	c.377C>T	p.Ala126Val	missense	Exon 5 of 11	ENSP00000440695.1	P20916-3
	MAG	ENST00000361922.8	TSL:1	c.452C>T	p.Ala151Val	missense	Exon 5 of 12	ENSP00000355234.4	P20916-2

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

GnomAD2 exomes AF: 0.00368 AC: 899 AN: 244414 AF XY: 0.00385

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 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

African (AFR) AF: 0.00112 AC: 37 AN: 33180

American (AMR) AF: 0.00185 AC: 82 AN: 44212

Ashkenazi Jewish (ASJ) AF: 0.000347 AC: 9 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39280

South Asian (SAS) AF: 0.00513 AC: 437 AN: 85240

European-Finnish (FIN) AF: 0.00102 AC: 54 AN: 53192

Middle Eastern (MID) AF: 0.00490 AC: 28 AN: 5720

European-Non Finnish (NFE) AF: 0.00633 AC: 6992 AN: 1104314

Other (OTH) AF: 0.00425 AC: 254 AN: 59774

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

African (AFR) AF: 0.00137 AC: 57 AN: 41506

American (AMR) AF: 0.00216 AC: 33 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00478 AC: 23 AN: 4816

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00703 AC: 478 AN: 67970

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00465 Hom.: 8

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 75 (1)
-	-	1	MAG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.37
Sift	Benign	0.071	T
Sift4G	Benign	0.10	T
Polyphen		0.98	D
Vest4		0.12
MVP		0.65
MPC		0.48
ClinPred		0.017	T
GERP RS		4.6
Varity_R		0.22
gMVP		0.56
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs144553163; hg19: chr19-35790493; COSMIC: COSV106108464;