Variant 2-237542658-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024101.7(MLPH):c.1538C>T(p.Pro513Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000555 in 1,566,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P513P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MLPH
NM_024101.7 missense, splice_region

Scores

Splicing: ADA: 0.9845

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.658

Variant links:

Genes affected

MLPH (HGNC:29643): (melanophilin) This gene encodes a member of the exophilin subfamily of Rab effector proteins. The protein forms a ternary complex with the small Ras-related GTPase Rab27A in its GTP-bound form and the motor protein myosin Va. A similar protein complex in mouse functions to tether pigment-producing organelles called melanosomes to the actin cytoskeleton in melanocytes, and is required for visible pigmentation in the hair and skin. A mutation in this gene results in Griscelli syndrome type 3, which is characterized by a silver-gray hair color and abnormal pigment distribution in the hair shaft. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

MLPH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLPH	NM_024101.7 linkuse as main transcript	c.1538C>T	p.Pro513Leu	missense_variant, splice_region_variant	12/16	ENST00000264605.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLPH	ENST00000264605.8 linkuse as main transcript	c.1538C>T	p.Pro513Leu	missense_variant, splice_region_variant	12/16	1	NM_024101.7	A2	Q9BV36-1

Frequencies

GnomAD3 genomes

AF:

0.000101

AC:

AN:

148340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

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:

0.0000744

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000853

AC:

AN:

175894

Hom.:

AF XY:

0.0000634

AC XY:

AN XY:

94594

show subpopulations

Gnomad AFR exome

AF:

0.0000989

Gnomad AMR exome

AF:

0.0000382

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000745

Gnomad SAS exome

AF:

0.0000417

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000152

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000508

AC:

AN:

1418126

Hom.:

Cov.:

AF XY:

0.0000527

AC XY:

AN XY:

701706

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.0000262

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000529

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.0000407

Gnomad4 NFE exome

AF:

0.0000550

Gnomad4 OTH exome

AF:

0.0000852

GnomAD4 genome

AF:

0.000101

AC:

AN:

148422

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

72218

show subpopulations

Gnomad4 AFR

AF:

0.000199

Gnomad4 AMR

AF:

0.000136

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000744

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000422

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 02, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.39

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.38

T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D

REVEL

Benign

0.12

Sift

Benign

0.15

T;T;T;D;D;T

Sift4G

Benign

0.076

T;T;T;T;T;T

Polyphen

1.0, 1.0

.;D;D;.;.;.

Vest4

0.26

MVP

0.58

MPC

0.48

ClinPred

0.48

GERP RS

4.1

Varity_R

0.57

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over