2-237525791-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLPH	NM_024101.7 link	c.866C>T	p.Thr289Ile	missense_variant	Exon 7 of 16	ENST00000264605.8	NP_077006.1	Q9BV36-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8 link	c.866C>T	p.Thr289Ile	missense_variant	Exon 7 of 16	1	NM_024101.7	ENSP00000264605.3		Q9BV36-1

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

GnomAD3 exomes

AF:

0.132

AC:

32840

AN:

248132

Hom.:

2513

AF XY:

0.132

AC XY:

17730

AN XY:

134656

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 SAS exome

AF:

0.0949

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

Gnomad4 AFR exome

AF:

0.237

Gnomad4 AMR exome

AF:

0.0690

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.0487

Gnomad4 SAS exome

AF:

0.100

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.167

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.167

AC:

25461

AN:

152230

Hom.:

2374

Cov.:

AF XY:

0.163

AC XY:

12123

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.233

Gnomad4 AMR

AF:

0.0970

Gnomad4 ASJ

AF:

0.134

Gnomad4 EAS

AF:

0.0554

Gnomad4 SAS

AF:

0.0933

Gnomad4 FIN

AF:

0.136

Gnomad4 NFE

AF:

0.164

Gnomad4 OTH

AF:

0.156

Alfa

AF:

0.155

Hom.:

3980

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

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

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

0.11

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.049

DANN

Benign

0.54

DEOGEN2

Benign

0.18

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.43

T;T;T

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.019

Sift

Benign

0.49

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.016

MPC

0.11

ClinPred

0.0036

GERP RS

-4.4

Varity_R

0.029

gMVP

0.10

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

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