chr2-237534583-A-G

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.1040A>G(p.His347Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,611,710 control chromosomes in the GnomAD database, including 64,663 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 0.34 ( 10381 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54282 hom. )

Consequence

MLPH
NM_024101.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.196

Publications

121 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=1.148294E-5).

BP6

Variant 2-237534583-A-G is Benign according to our data. Variant chr2-237534583-A-G is described in ClinVar as Benign. ClinVar VariationId is 1229855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLPH	NM_024101.7 link	c.1040A>G	p.His347Arg	missense_variant	Exon 9 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.1040A>G	p.His347Arg	missense_variant	Exon 9 of 16	1	NM_024101.7	ENSP00000264605.3

Frequencies

GnomAD3 genomes

AF:

0.340

AC:

51597

AN:

151856

Hom.:

10354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.565

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.256

Gnomad EAS

AF:

0.272

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.317

GnomAD2 exomes

AF:

0.284

AC:

71311

AN:

251392

AF XY:

0.279

show subpopulations

Gnomad AFR exome

AF:

0.578

Gnomad AMR exome

AF:

0.294

Gnomad ASJ exome

AF:

0.270

Gnomad EAS exome

AF:

0.270

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.255

GnomAD4 exome

AF:

0.265

AC:

387415

AN:

1459736

Hom.:

54282

Cov.:

AF XY:

0.267

AC XY:

193562

AN XY:

726300

show subpopulations

African (AFR)

AF:

0.582

AC:

19451

AN:

33416

American (AMR)

AF:

0.297

AC:

13262

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

6907

AN:

26112

East Asian (EAS)

AF:

0.260

AC:

10327

AN:

39660

South Asian (SAS)

AF:

0.340

AC:

29317

AN:

86206

European-Finnish (FIN)

AF:

0.203

AC:

10825

AN:

53364

Middle Eastern (MID)

AF:

0.298

AC:

1716

AN:

5754

European-Non Finnish (NFE)

AF:

0.251

AC:

278375

AN:

1110242

Other (OTH)

AF:

0.286

AC:

17235

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

14507

29013

43520

58026

72533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9768

19536

29304

39072

48840

<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:

0.340

AC:

51678

AN:

151974

Hom.:

10381

Cov.:

AF XY:

0.336

AC XY:

24933

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.565

AC:

23385

AN:

41394

American (AMR)

AF:

0.310

AC:

4727

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

888

AN:

3470

East Asian (EAS)

AF:

0.272

AC:

1403

AN:

5160

South Asian (SAS)

AF:

0.341

AC:

1643

AN:

4818

European-Finnish (FIN)

AF:

0.191

AC:

2022

AN:

10562

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.245

AC:

16672

AN:

67984

Other (OTH)

AF:

0.319

AC:

674

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1579

3158

4737

6316

7895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.275

Hom.:

30773

Bravo

AF:

0.356

TwinsUK

AF:

0.257

AC:

954

ALSPAC

AF:

0.256

AC:

987

ESP6500AA

AF:

0.568

AC:

2503

ESP6500EA

AF:

0.255

AC:

2189

ExAC

AF:

0.289

AC:

35088

Asia WGS

AF:

0.302

AC:

1050

AN:

3478

EpiCase

AF:

0.242

EpiControl

AF:

0.244

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21743057) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.044

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.081

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.000011

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.0

N;.

PhyloP100

0.20

PrimateAI

Benign

0.18

PROVEAN

Benign

0.82

N;N

REVEL

Benign

0.036

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.026

MPC

0.13

ClinPred

0.00098

GERP RS

0.013

Varity_R

0.030

gMVP

0.080

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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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