2-237542658-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Griscelli syndrome type 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

MLPH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious 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 rank	MANE	Protein	UniProt
MLPH	NM_024101.7 link	c.1538C>T	p.Pro513Leu	missense_variant, splice_region_variant	Exon 12 of 16	ENST00000264605.8	NP_077006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8 link	c.1538C>T	p.Pro513Leu	missense_variant, splice_region_variant	Exon 12 of 16	1	NM_024101.7	ENSP00000264605.3

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

GnomAD2 exomes

AF:

0.0000853

AC:

AN:

175894

AF XY:

0.0000634

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 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

African (AFR)

AF:

0.0000305

AC:

AN:

32750

American (AMR)

AF:

0.0000262

AC:

AN:

38172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.0000529

AC:

AN:

37808

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81092

European-Finnish (FIN)

AF:

0.0000407

AC:

AN:

49166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5116

European-Non Finnish (NFE)

AF:

0.0000550

AC:

AN:

1089952

Other (OTH)

AF:

0.0000852

AC:

AN:

58706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000101

AC:

AN:

148422

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

72218

show subpopulations

African (AFR)

AF:

0.000199

AC:

AN:

40162

American (AMR)

AF:

0.000136

AC:

AN:

14722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

4986

South Asian (SAS)

AF:

0.00

AC:

AN:

4672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000744

AC:

AN:

67170

Other (OTH)

AF:

0.00

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Dec 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

.;T;.;.;T;.

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

MutationAssessor

Uncertain

2.6

.;M;.;.;.;.

PhyloP100

0.66

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

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over