Genetic Variant NM_024101.7:c.1040A>T (chr2-237534583-A-T) – 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.1040A>T(p.His347Leu) variant causes a missense 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. 16/22 in silico tools predict a benign outcome for this variant. 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. H347R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MLPH
NM_024101.7 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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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=0.0535838).

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.1040A>T	p.His347Leu	missense	Exon 9 of 16	NP_077006.1
MLPH	NR_104019.2		n.1251A>T		non_coding_transcript_exon	Exon 9 of 17
MLPH	NM_001042467.3		c.1021-5765A>T		intron	N/A	NP_001035932.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLPH	ENST00000264605.8	TSL:1 MANE Select	c.1040A>T	p.His347Leu	missense	Exon 9 of 16	ENSP00000264605.3
MLPH	ENST00000338530.8	TSL:1	c.1021-5765A>T		intron	N/A	ENSP00000341845.4
MLPH	ENST00000409373.5	TSL:1	c.901-5765A>T		intron	N/A	ENSP00000386780.1

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

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.0

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.28

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.44

M_CAP

Benign

0.0036

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.20

PrimateAI

Benign

0.18

PROVEAN

Benign

-1.8

REVEL

Benign

0.042

Sift

Uncertain

0.0070

Sift4G

Benign

0.067

Polyphen

0.0010

Vest4

0.27

MutPred

0.34

Loss of disorder (P = 0.0606)

MVP

0.32

MPC

0.13

ClinPred

0.066

GERP RS

0.013

Varity_R

0.12

gMVP

0.21

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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