NM_000533.5:c.-31C>T

Variant names:

• chrX-103776965-C-T
• rs2233695
• NM_000533.5:c.-31C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000533.5(PLP1):​c.-31C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,197,630 control chromosomes in the GnomAD database, including 10 homozygotes. There are 543 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., 62 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (8 hom. 481 hem.)
• Consequence: PLP1 NM_000533.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 0.394
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant X-103776965-C-T is Benign according to our data. Variant chrX-103776965-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0019 (213/111817) while in subpopulation EAS AF = 0.0224 (79/3531). AF 95% confidence interval is 0.0184. There are 2 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

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.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_000524.3
	PLP1	NM_000533.5	MANE Select	c.-31C>T		5_prime_UTR	Exon 1 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001122306.1	A8K9L3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000477619.1	P60201-2
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.-31C>T		5_prime_UTR	Exon 1 of 7	ENSP00000484450.1	P60201-1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 204 AN: 111767 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00737

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.000989

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.00463

GnomAD2 exomes AF: 0.00343 AC: 619 AN: 180671 AF XY: 0.00243

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0180

Gnomad FIN exome AF: 0.000818

Gnomad NFE exome AF: 0.000224

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.00144 AC: 1566 AN: 1085813 Hom.: 8 Cov.: 27 AF XY: 0.00136 AC XY: 481 AN XY: 352643

African (AFR) AF: 0.000153 AC: 4 AN: 26177

American (AMR) AF: 0.0121 AC: 424 AN: 35132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19297

East Asian (EAS) AF: 0.0226 AC: 680 AN: 30090

South Asian (SAS) AF: 0.00123 AC: 66 AN: 53583

European-Finnish (FIN) AF: 0.00168 AC: 68 AN: 40493

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.000283 AC: 235 AN: 831257

Other (OTH) AF: 0.00195 AC: 89 AN: 45694

GnomAD4 genome AF: 0.00190 AC: 213 AN: 111817 Hom.: 2 Cov.: 23 AF XY: 0.00182 AC XY: 62 AN XY: 34033

African (AFR) AF: 0.000227 AC: 7 AN: 30816

American (AMR) AF: 0.00727 AC: 77 AN: 10591

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.0224 AC: 79 AN: 3531

South Asian (SAS) AF: 0.00188 AC: 5 AN: 2654

European-Finnish (FIN) AF: 0.000989 AC: 6 AN: 6067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000414 AC: 22 AN: 53082

Other (OTH) AF: 0.0111 AC: 17 AN: 1531

Alfa AF: 0.00148 Hom.: 63

Bravo AF: 0.00238

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary spastic paraplegia 2 (1)
-	-	1	not specified (1)
-	-	1	Pelizaeus-Merzbacher disease (1)
-	1	-	Pelizaeus-Merzbacher disease, mild (1)
-	-	1	Pelizaeus-Merzbacher disease;C0751604:Hereditary spastic paraplegia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		0.39
PromoterAI		-0.22	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2233695; hg19: chrX-103031893;