2-237510629-A-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024101.7(MLPH):c.166A>T(p.Thr56Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MLPH
NM_024101.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06750357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLPH	NM_024101.7 link	c.166A>T	p.Thr56Ser	missense_variant	Exon 3 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.166A>T	p.Thr56Ser	missense_variant	Exon 3 of 16	1	NM_024101.7	ENSP00000264605.3		Q9BV36-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152230

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251164

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135862

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461384

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726992

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:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166A>T (p.T56S) alteration is located in exon 3 (coding exon 2) of the MLPH gene. This alteration results from a A to T substitution at nucleotide position 166, causing the threonine (T) at amino acid position 56 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.41

CADD

Benign

4.8

DANN

Benign

0.74

DEOGEN2

Benign

0.21

T;.;.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.71

T;T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.068

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.28

.;.;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.87

T;T;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T;T

Polyphen

0.0010, 0.0020

.;.;.;B;B;.

Vest4

0.071, 0.065, 0.11, 0.097

MutPred

0.32

Loss of glycosylation at T56 (P = 0.038);Loss of glycosylation at T56 (P = 0.038);Loss of glycosylation at T56 (P = 0.038);Loss of glycosylation at T56 (P = 0.038);Loss of glycosylation at T56 (P = 0.038);Loss of glycosylation at T56 (P = 0.038);

MVP

0.52

MPC

0.092

ClinPred

0.042

GERP RS

-7.9

Varity_R

0.040

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

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

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