rs11883500

Variant names:

• chr2-237525791-C-A
• rs11883500
• NM_024101.7:c.866C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-237525791-C-A
• chr2-237525791-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024101.7(MLPH):​c.866C>A​(p.Thr289Asn) 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. 14/18 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. T289I) 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: -2.22
• Publications: 20 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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=0.064305454).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	NM_024101.7	MANE Select	c.866C>A	p.Thr289Asn	missense	Exon 7 of 16	NP_077006.1
	MLPH	NM_001042467.3		c.866C>A	p.Thr289Asn	missense	Exon 7 of 15	NP_001035932.1
	MLPH	NM_001281473.2		c.746C>A	p.Thr249Asn	missense	Exon 6 of 13	NP_001268402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	ENST00000264605.8	TSL:1 MANE Select	c.866C>A	p.Thr289Asn	missense	Exon 7 of 16	ENSP00000264605.3
	MLPH	ENST00000338530.8	TSL:1	c.866C>A	p.Thr289Asn	missense	Exon 7 of 15	ENSP00000341845.4
	MLPH	ENST00000409373.5	TSL:1	c.746C>A	p.Thr249Asn	missense	Exon 6 of 13	ENSP00000386780.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 7628

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.015
DANN	Benign	0.39
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.2
PROVEAN	Benign	0.50	N
REVEL	Benign	0.010
Sift	Uncertain	0.011	D
Sift4G	Benign	0.26	T
MutPred		0.29		Loss of catalytic residue at L96 (P = 5e-04)
MVP		0.099
ClinPred		0.36	T
GERP RS		-4.4
PromoterAI		0.0023	Neutral
Varity_R		0.040
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11883500; hg19: chr2-238434434;