rs1126707

Variant names:

• chrX-103787953-T-C
• rs1126707
• NM_000533.5:c.609T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000533.5(PLP1):​c.609T>C​(p.Asp203Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,206,198 control chromosomes in the GnomAD database, including 35,090 homozygotes. There are 111,962 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (2706 hom., 7800 hem., cov: 23)
  • Exomes 𝑓: 0.29 (32384 hom. 104162 hem.)
• Consequence: PLP1 NM_000533.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.61
• Publications: 14 publications found

Genes affected

PLP1 (HGNC:9086): (proteolipid protein 1) This gene encodes a transmembrane proteolipid protein that is the predominant component of myelin. The encoded protein may play a role in the compaction, stabilization, and maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival. Mutations in this gene cause Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Alternatively splicing results in multiple transcript variants, including the DM20 splice variant. [provided by RefSeq, Feb 2015]

ENSG00000288597 (HGNC:):

RAB9B (HGNC:14090): (RAB9B, member RAS oncogene family) This gene encodes a member of a subfamily of RAS small guanosine triphosphate (GTP)-binding proteins that regulate membrane trafficking. The encoded protein may be involved in endosome-to-Golgi transport. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-103787953-T-C is Benign according to our data. Variant chrX-103787953-T-C is described in ClinVar as Benign. ClinVar VariationId is 93232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000533.5. 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
	PLP1	NM_000533.5	MANE Select	c.609T>C	p.Asp203Asp	synonymous	Exon 4 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.609T>C	p.Asp203Asp	synonymous	Exon 5 of 8	NP_001122306.1	A8K9L3
	PLP1	NM_199478.3		c.504T>C	p.Asp168Asp	synonymous	Exon 4 of 7	NP_955772.1	P60201-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.609T>C	p.Asp203Asp	synonymous	Exon 4 of 7	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.504T>C	p.Asp168Asp	synonymous	Exon 4 of 7	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.651T>C	p.Asp217Asp	synonymous	Exon 5 of 8	ENSP00000537771.1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 27110 AN: 111427 Hom.: 2708 Cov.: 23

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.285 AC: 52242 AN: 183021 AF XY: 0.280

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.291 AC: 319080 AN: 1094715 Hom.: 32384 Cov.: 30 AF XY: 0.289 AC XY: 104162 AN XY: 360679

African (AFR) AF: 0.113 AC: 2969 AN: 26342

American (AMR) AF: 0.400 AC: 14079 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 6858 AN: 19362

East Asian (EAS) AF: 0.269 AC: 8116 AN: 30184

South Asian (SAS) AF: 0.199 AC: 10758 AN: 54077

European-Finnish (FIN) AF: 0.258 AC: 10463 AN: 40500

Middle Eastern (MID) AF: 0.209 AC: 857 AN: 4095

European-Non Finnish (NFE) AF: 0.300 AC: 251986 AN: 838984

Other (OTH) AF: 0.283 AC: 12994 AN: 45993

GnomAD4 genome AF: 0.243 AC: 27104 AN: 111483 Hom.: 2706 Cov.: 23 AF XY: 0.232 AC XY: 7800 AN XY: 33689

African (AFR) AF: 0.116 AC: 3580 AN: 30745

American (AMR) AF: 0.328 AC: 3445 AN: 10518

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 975 AN: 2630

East Asian (EAS) AF: 0.253 AC: 888 AN: 3515

South Asian (SAS) AF: 0.170 AC: 452 AN: 2655

European-Finnish (FIN) AF: 0.230 AC: 1383 AN: 6009

Middle Eastern (MID) AF: 0.155 AC: 34 AN: 219

European-Non Finnish (NFE) AF: 0.298 AC: 15797 AN: 52989

Other (OTH) AF: 0.268 AC: 409 AN: 1526

Alfa AF: 0.286 Hom.: 10440

Bravo AF: 0.249

EpiCase AF: 0.296

EpiControl AF: 0.294

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Hereditary spastic paraplegia 2 (2)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Pelizaeus-Merzbacher disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		1.6
Mutation Taster		=99/1	polymorphism (auto)

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: rs1126707; hg19: chrX-103042882; COSMIC: COSV58276358; COSMIC: COSV58276358;