2-237542657-CC-TT

Variant names:

• chr2-237542657-CC-TT
• NM_024101.7:c.1537_1538delCCinsTT
• MLPH p.Pro513Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_024101.7(MLPH):​c.1537_1538delCCinsTT​(p.Pro513Leu) 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. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P513P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLPH NM_024101.7 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.14
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	NM_024101.7	MANE Select	c.1537_1538delCCinsTT	p.Pro513Leu	missense splice_region	N/A	NP_077006.1	Q9BV36-1
	MLPH	NM_001042467.3		c.1453_1454delCCinsTT	p.Pro485Leu	missense splice_region	N/A	NP_001035932.1	Q9BV36-2
	MLPH	NM_001281473.2		c.1177_1178delCCinsTT	p.Pro393Leu	missense splice_region	N/A	NP_001268402.1	Q9BV36-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	ENST00000264605.8	TSL:1 MANE Select	c.1537_1538delCCinsTT	p.Pro513Leu	missense splice_region	N/A	ENSP00000264605.3	Q9BV36-1
	MLPH	ENST00000338530.8	TSL:1	c.1453_1454delCCinsTT	p.Pro485Leu	missense splice_region	N/A	ENSP00000341845.4	Q9BV36-2
	MLPH	ENST00000409373.5	TSL:1	c.1177_1178delCCinsTT	p.Pro393Leu	missense splice_region	N/A	ENSP00000386780.1	Q9BV36-3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-238451300;