rs369604551

Positions:

• chr2-237542658-C-A
• chr2-237542658-C-G
• chr2-237542658-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024101.7(MLPH):​c.1538C>A​(p.Pro513Gln) 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. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLPH NM_024101.7 missense, splice_region
• Scores: Splicing: ADA: 0.003776
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.658

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22728688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLPH	NM_024101.7	c.1538C>A	p.Pro513Gln	missense_variant, splice_region_variant	12/16	ENST00000264605.8	NP_077006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8	c.1538C>A	p.Pro513Gln	missense_variant, splice_region_variant	12/16	1	NM_024101.7	ENSP00000264605	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	.;T;.;.;T;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;.;.;.;.
MutationTaster	Benign	0.92	N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.69	T;T;T;T;T;T
Sift4G	Benign	0.94	T;T;T;T;T;T
Polyphen		0.60, 0.72	.;P;P;.;.;.
Vest4		0.28
MutPred		0.34		.;Loss of glycosylation at P513 (P = 0.0839);.;.;.;.;
MVP		0.46
MPC		0.20
ClinPred		0.86	D
GERP RS		4.1
Varity_R		0.14
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0038
dbscSNV1_RF	Benign	0.074
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

Other links and lift over

dbSNP: rs369604551; hg19: chr2-238451301;