19-35302594-A-C

Variant names:

• chr19-35302594-A-C
• rs142375870
• NM_002361.4:c.1117A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002361.4(MAG):​c.1117A>C​(p.Ser373Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000147 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S373S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.41
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0404177).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00023 (35/152296) while in subpopulation AMR AF = 0.00118 (18/15308). AF 95% confidence interval is 0.00076. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1117A>C	p.Ser373Arg	missense	Exon 7 of 11	NP_002352.1	P20916-1
	MAG	NM_001199216.2		c.1042A>C	p.Ser348Arg	missense	Exon 7 of 11	NP_001186145.1	P20916-3
	MAG	NM_080600.3		c.1117A>C	p.Ser373Arg	missense	Exon 7 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.1117A>C	p.Ser373Arg	missense	Exon 7 of 11	ENSP00000376048.2	P20916-1
	MAG	ENST00000537831.2	TSL:1	c.1042A>C	p.Ser348Arg	missense	Exon 7 of 11	ENSP00000440695.1	P20916-3
	MAG	ENST00000361922.8	TSL:1	c.1117A>C	p.Ser373Arg	missense	Exon 7 of 12	ENSP00000355234.4	P20916-2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251468 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 94 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1112012

Other (OTH) AF: 0.000430 AC: 26 AN: 60396

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74452

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary spastic paraplegia 75 (2)
-	1	-	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.040	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.62	N
PhyloP100		4.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.47
Sift	Benign	0.068	T
Sift4G	Benign	0.079	T
Polyphen		0.97	D
Vest4		0.27
MutPred		0.31		Gain of solvent accessibility (P = 0.0365)
MVP		0.74
MPC		1.1
ClinPred		0.13	T
GERP RS		5.1
Varity_R		0.29
gMVP		0.81
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs142375870; hg19: chr19-35793497;