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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_024101.7(MLPH):c.1538C>G(p.Pro513Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,566,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P513L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MLPH
NM_024101.7 missense, splice_region

Scores

Splicing: ADA: 0.5425

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35848352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLPH	NM_024101.7 linkuse as main transcript	c.1538C>G	p.Pro513Arg	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>G	p.Pro513Arg	missense_variant, splice_region_variant	12/16	1	NM_024101.7	A2	Q9BV36-1

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148344

Hom.:

Cov.:

show subpopulations

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:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000171

AC:

AN:

175894

Hom.:

AF XY:

0.0000211

AC XY:

AN XY:

94594

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000414

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000106

AC:

AN:

1418132

Hom.:

Cov.:

AF XY:

0.0000128

AC XY:

AN XY:

701706

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000138

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72126

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000298

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000169

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.39

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.88

D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.36

T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationTaster

Benign

0.53

D;D;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D

REVEL

Benign

0.11

Sift

Benign

0.93

T;T;T;T;T;T

Sift4G

Benign

0.46

T;T;T;T;T;T

Polyphen

0.87, 0.83

.;P;P;.;.;.

Vest4

0.35

MutPred

0.36

.;Gain of solvent accessibility (P = 0.0411);.;.;.;.;

MVP

0.55

MPC

0.31

ClinPred

0.96

GERP RS

4.1

Varity_R

0.28

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.54

dbscSNV1_RF

Benign

0.54

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over