chr7-40132833-C-T

Variant names:

• chr7-40132833-C-T
• rs11974850
• NM_138701.4:c.*226G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138701.4(MPLKIP):​c.*226G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 549,930 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: MPLKIP NM_138701.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0730
• Publications: 0 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-40132833-C-T is Benign according to our data. Variant chr7-40132833-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1187139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00906 (1378/152148) while in subpopulation AFR AF = 0.0306 (1271/41500). AF 95% confidence interval is 0.0292. There are 18 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138701.4. 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
	MPLKIP	NM_138701.4	MANE Select	c.*226G>A		3_prime_UTR	Exon 2 of 2	NP_619646.1	Q8TAP9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPLKIP	ENST00000306984.8	TSL:1 MANE Select	c.*226G>A		3_prime_UTR	Exon 2 of 2	ENSP00000304553.5	Q8TAP9

Frequencies

GnomAD3 genomes AF: 0.00901 AC: 1370 AN: 152032 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.00132 AC: 527 AN: 397782 Hom.: 8 Cov.: 3 AF XY: 0.00109 AC XY: 231 AN XY: 211916

African (AFR) AF: 0.0297 AC: 340 AN: 11442

American (AMR) AF: 0.00277 AC: 46 AN: 16582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12092

East Asian (EAS) AF: 0.0000381 AC: 1 AN: 26234

South Asian (SAS) AF: 0.0000922 AC: 4 AN: 43392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23282

Middle Eastern (MID) AF: 0.00406 AC: 7 AN: 1724

European-Non Finnish (NFE) AF: 0.000246 AC: 59 AN: 240012

Other (OTH) AF: 0.00304 AC: 70 AN: 23022

GnomAD4 genome AF: 0.00906 AC: 1378 AN: 152148 Hom.: 18 Cov.: 33 AF XY: 0.00851 AC XY: 633 AN XY: 74362

African (AFR) AF: 0.0306 AC: 1271 AN: 41500

American (AMR) AF: 0.00465 AC: 71 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67982

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00632 Hom.: 2

Bravo AF: 0.0105

Asia WGS AF: 0.00491 AC: 18 AN: 3474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.60
PhyloP100		0.073
Mutation Taster		=100/0	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: rs11974850; hg19: chr7-40172432;