NM_024101.7:c.180C>A

Variant names:

• chr2-237510643-C-A
• rs2292878
• NM_024101.7:c.180C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024101.7(MLPH):​c.180C>A​(p.Asn60Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N60N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLPH NM_024101.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.84
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.180C>A	p.Asn60Lys	missense	Exon 3 of 16	NP_077006.1	Q9BV36-1
	MLPH	NM_001042467.3		c.180C>A	p.Asn60Lys	missense	Exon 3 of 15	NP_001035932.1	Q9BV36-2
	MLPH	NM_001281473.2		c.180C>A	p.Asn60Lys	missense	Exon 3 of 13	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.180C>A	p.Asn60Lys	missense	Exon 3 of 16	ENSP00000264605.3	Q9BV36-1
	MLPH	ENST00000338530.8	TSL:1	c.180C>A	p.Asn60Lys	missense	Exon 3 of 15	ENSP00000341845.4	Q9BV36-2
	MLPH	ENST00000409373.5	TSL:1	c.180C>A	p.Asn60Lys	missense	Exon 3 of 13	ENSP00000386780.1	Q9BV36-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	4.0
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	L
PhyloP100		-4.8
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.37
Sift	Benign	0.067	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.46		Gain of ubiquitination at N60 (P = 0.0069)
MVP		0.76
MPC		0.19
ClinPred		0.96	D
GERP RS		-0.88
Varity_R		0.54
gMVP		0.29
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs2292878; hg19: chr2-238419286;