2-237525791-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024101.7(MLPH):c.866C>T(p.Thr289Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,612,474 control chromosomes in the GnomAD database, including 21,276 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2374 hom., cov: 33)

Exomes 𝑓: 0.16 ( 18902 hom. )

Consequence

MLPH
NM_024101.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.22

Publications

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0038525462).

BP6

Variant 2-237525791-C-T is Benign according to our data. Variant chr2-237525791-C-T is described in ClinVar as Benign. ClinVar VariationId is 1279299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024101.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLPH	NM_024101.7	MANE Select	c.866C>T	p.Thr289Ile	missense	Exon 7 of 16	NP_077006.1
MLPH	NM_001042467.3		c.866C>T	p.Thr289Ile	missense	Exon 7 of 15	NP_001035932.1
MLPH	NM_001281473.2		c.746C>T	p.Thr249Ile	missense	Exon 6 of 13	NP_001268402.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLPH	ENST00000264605.8	TSL:1 MANE Select	c.866C>T	p.Thr289Ile	missense	Exon 7 of 16	ENSP00000264605.3
MLPH	ENST00000338530.8	TSL:1	c.866C>T	p.Thr289Ile	missense	Exon 7 of 15	ENSP00000341845.4
MLPH	ENST00000409373.5	TSL:1	c.746C>T	p.Thr249Ile	missense	Exon 6 of 13	ENSP00000386780.1

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25433

AN:

152112

Hom.:

2368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.0972

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.0554

Gnomad SAS

AF:

0.0931

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.164

Gnomad OTH

AF:

0.159

GnomAD2 exomes

AF:

0.132

AC:

32840

AN:

248132

AF XY:

0.132

show subpopulations

Gnomad AFR exome

AF:

0.228

Gnomad AMR exome

AF:

0.0643

Gnomad ASJ exome

AF:

0.143

Gnomad EAS exome

AF:

0.0543

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.161

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.157

AC:

228722

AN:

1460244

Hom.:

18902

Cov.:

AF XY:

0.155

AC XY:

112627

AN XY:

726510

show subpopulations

African (AFR)

AF:

0.237

AC:

7919

AN:

33464

American (AMR)

AF:

0.0690

AC:

3084

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3719

AN:

26132

East Asian (EAS)

AF:

0.0487

AC:

1935

AN:

39700

South Asian (SAS)

AF:

0.100

AC:

8650

AN:

86236

European-Finnish (FIN)

AF:

0.141

AC:

7339

AN:

52216

Middle Eastern (MID)

AF:

0.111

AC:

612

AN:

5526

European-Non Finnish (NFE)

AF:

0.167

AC:

186064

AN:

1111912

Other (OTH)

AF:

0.156

AC:

9400

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

11023

22046

33069

44092

55115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6578

13156

19734

26312

32890

<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:

0.167

AC:

25461

AN:

152230

Hom.:

2374

Cov.:

AF XY:

0.163

AC XY:

12123

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.233

AC:

9684

AN:

41526

American (AMR)

AF:

0.0970

AC:

1483

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

465

AN:

3472

East Asian (EAS)

AF:

0.0554

AC:

287

AN:

5182

South Asian (SAS)

AF:

0.0933

AC:

451

AN:

4832

European-Finnish (FIN)

AF:

0.136

AC:

1437

AN:

10600

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.164

AC:

11146

AN:

68002

Other (OTH)

AF:

0.156

AC:

331

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1094

2189

3283

4378

5472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.158

Hom.:

7628

Bravo

AF:

0.167

TwinsUK

AF:

0.167

AC:

618

ALSPAC

AF:

0.176

AC:

678

ESP6500AA

AF:

0.237

AC:

1044

ESP6500EA

AF:

0.167

AC:

1434

ExAC

AF:

0.136

AC:

16502

Asia WGS

AF:

0.0770

AC:

271

AN:

3478

EpiCase

AF:

0.150

EpiControl

AF:

0.154

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.049

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.18

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-2.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

REVEL

Benign

0.019

Sift

Benign

0.49

Sift4G

Benign

0.21

Polyphen

0.0040

Vest4

0.016

MPC

0.11

ClinPred

0.0036

GERP RS

-4.4

PromoterAI

-0.0063

Neutral

(source)

Varity_R

0.029

gMVP

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over