7-40134228-C-T

Variant names:

• chr7-40134228-C-T
• rs869312900
• NM_138701.4:c.339+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138701.4(MPLKIP):​c.339+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MPLKIP NM_138701.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.57
• Publications: 3 publications found

Genes affected

MPLKIP (HGNC:16002): (M-phase specific PLK1 interacting protein) The protein encoded by this gene localizes to the centrosome during mitosis and to the midbody during cytokinesis. The protein is phosphorylated by cyclin-dependent kinase 1 during mitosis and subsequently interacts with polo-like kinase 1. The protein is thought to function in regulating mitosis and cytokinesis. Mutations in this gene result in nonphotosensitive trichothiodystrophy. [provided by RefSeq, Nov 2009]

MPLKIP Gene-Disease associations (from GenCC):

• trichothiodystrophy 4, nonphotosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-40134228-C-T is Pathogenic according to our data. Variant chr7-40134228-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 224867.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPLKIP	NM_138701.4	c.339+1G>A		splice_donor_variant, intron_variant	Intron 1 of 1	ENST00000306984.8	NP_619646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPLKIP	ENST00000306984.8	c.339+1G>A		splice_donor_variant, intron_variant	Intron 1 of 1	1	NM_138701.4	ENSP00000304553.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 151972 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401430 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691454

African (AFR) AF: 0.00 AC: 0 AN: 31774

American (AMR) AF: 0.00 AC: 0 AN: 36018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36026

South Asian (SAS) AF: 0.00 AC: 0 AN: 79440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080384

Other (OTH) AF: 0.00 AC: 0 AN: 58078

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Trichothiodystrophy 4, nonphotosensitive Pathogenic:1

Feb 01, 2016

Department of Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		3.6
GERP RS		3.7
PromoterAI		-0.19	Neutral
Mutation Taster		=69/31	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -49
DS_DL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869312900; hg19: chr7-40173827;