19-35295609-G-T

Position:

• chr19-35295609-G-T

Variant summary

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

The NM_002361.4(MAG):​c.47-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,598,704 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (63 hom.)
• Consequence: MAG NM_002361.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005542
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.663

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-35295609-G-T is Benign according to our data. Variant chr19-35295609-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 252776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00616 (938/152254) while in subpopulation NFE AF= 0.00943 (641/68008). AF 95% confidence interval is 0.00882. There are 4 homozygotes in gnomad4. There are 411 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAG	NM_002361.4	c.47-4G>T		splice_region_variant, intron_variant		ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.-29-4G>T		splice_region_variant, intron_variant			NP_001186145.1
MAG	NM_080600.3	c.47-4G>T		splice_region_variant, intron_variant			NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.47-4G>T		splice_region_variant, intron_variant		1	NM_002361.4	ENSP00000376048.2

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 940 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00942

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00610 AC: 1457 AN: 238742 Hom.: 11 AF XY: 0.00630 AC XY: 811 AN XY: 128754

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000703

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00900

Gnomad OTH exome AF: 0.00724

GnomAD4 exome AF: 0.00878 AC: 12707 AN: 1446450 Hom.: 63 Cov.: 31 AF XY: 0.00856 AC XY: 6146 AN XY: 718400

Gnomad4 AFR exome AF: 0.000989

Gnomad4 AMR exome AF: 0.00470

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000878

Gnomad4 FIN exome AF: 0.00398

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00804

GnomAD4 genome AF: 0.00616 AC: 938 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00552 AC XY: 411 AN XY: 74442

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00943

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00539 Hom.: 1

Bravo AF: 0.00657

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MAG: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 30, 2015

- -

Hereditary spastic paraplegia 75 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.48
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00055
dbscSNV1_RF	Benign	0.022
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: rs147119099; hg19: chr19-35786512;