17-17136280-G-T

Variant names:

• chr17-17136280-G-T
• rs1266354453
• NM_001364716.4:c.566G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001364716.4(MPRIP):​c.566G>T​(p.Ser189Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,418,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MPRIP NM_001364716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.407
• Publications: 2 publications found

Genes affected

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11911139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPRIP	NM_001364716.4	c.566G>T	p.Ser189Ile	missense_variant	Exon 6 of 24	ENST00000651222.2	NP_001351645.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPRIP	ENST00000651222.2	c.566G>T	p.Ser189Ile	missense_variant	Exon 6 of 24		NM_001364716.4	ENSP00000498253.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 141090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245994 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1418620 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 703440

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32284

American (AMR) AF: 0.0000491 AC: 2 AN: 40762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 37160

South Asian (SAS) AF: 0.00 AC: 0 AN: 82758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5486

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084104

Other (OTH) AF: 0.00 AC: 0 AN: 58732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 141090 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 68458

African (AFR) AF: 0.00 AC: 0 AN: 38012

American (AMR) AF: 0.00 AC: 0 AN: 14022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00 AC: 0 AN: 4530

South Asian (SAS) AF: 0.00 AC: 0 AN: 4298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64324

Other (OTH) AF: 0.00 AC: 0 AN: 1942

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566G>T (p.S189I) alteration is located in exon 6 (coding exon 6) of the MPRIP gene. This alteration results from a G to T substitution at nucleotide position 566, causing the serine (S) at amino acid position 189 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	.;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		0.41
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.034
Sift	Uncertain	0.0050	D;D;.
Sift4G	Benign	0.079	T;T;D
Polyphen		0.87	P;P;.
Vest4		0.31
MutPred		0.28		Loss of phosphorylation at S189 (P = 8e-04);Loss of phosphorylation at S189 (P = 8e-04);.;
MVP		0.082
MPC		0.84
ClinPred		0.52	D
PromoterAI		0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.56

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: rs1266354453; hg19: chr17-17039594; COSMIC: COSV59046944; COSMIC: COSV59046944;