Genetic Variant MLPH:p.Ala38Gly (chr2-237510576-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024101.7(MLPH):c.113C>G(p.Ala38Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A38V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

MLPH
NM_024101.7 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.757

Publications

0 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: Orphanet, Labcorp Genetics (formerly Invitae)

MLPH links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017428935).

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	UniProt
MLPH	NM_024101.7	MANE Select	c.113C>G	p.Ala38Gly	missense splice_region	Exon 3 of 16	NP_077006.1	Q9BV36-1
MLPH	NM_001042467.3		c.113C>G	p.Ala38Gly	missense splice_region	Exon 3 of 15	NP_001035932.1	Q9BV36-2
MLPH	NM_001281473.2		c.113C>G	p.Ala38Gly	missense splice_region	Exon 3 of 13	NP_001268402.1	Q9BV36-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLPH	ENST00000264605.8	TSL:1 MANE Select	c.113C>G	p.Ala38Gly	missense splice_region	Exon 3 of 16	ENSP00000264605.3	Q9BV36-1
MLPH	ENST00000338530.8	TSL:1	c.113C>G	p.Ala38Gly	missense splice_region	Exon 3 of 15	ENSP00000341845.4	Q9BV36-2
MLPH	ENST00000409373.5	TSL:1	c.113C>G	p.Ala38Gly	missense splice_region	Exon 3 of 13	ENSP00000386780.1	Q9BV36-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

2.2

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.16

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.29

M_CAP

Benign

0.0060

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

PhyloP100

0.76

PrimateAI

Benign

0.24

PROVEAN

Benign

2.3

REVEL

Benign

0.14

Sift

Benign

0.31

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.079

MutPred

0.25

Loss of helix (P = 0.0444)

MVP

0.46

MPC

0.10

ClinPred

0.28

GERP RS

1.6

Varity_R

0.039

gMVP

0.22

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over