rs2292883

Variant names:

• chr2-237534357-C-T
• rs2292883
• NM_024101.7:c.1021-207C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024101.7(MLPH):​c.1021-207C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,180 control chromosomes in the GnomAD database, including 973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.10 (973 hom., cov: 32)
• Consequence: MLPH NM_024101.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.94
• Publications: 3 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-237534357-C-T is Benign according to our data. Variant chr2-237534357-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288073.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

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.1021-207C>T		intron	N/A	NP_077006.1	Q9BV36-1
	MLPH	NM_001042467.3		c.1021-5991C>T		intron	N/A	NP_001035932.1	Q9BV36-2
	MLPH	NM_001281473.2		c.901-5991C>T		intron	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.1021-207C>T		intron	N/A	ENSP00000264605.3	Q9BV36-1
	MLPH	ENST00000338530.8	TSL:1	c.1021-5991C>T		intron	N/A	ENSP00000341845.4	Q9BV36-2
	MLPH	ENST00000409373.5	TSL:1	c.901-5991C>T		intron	N/A	ENSP00000386780.1	Q9BV36-3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15719 AN: 152062 Hom.: 967 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0553

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0789

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.103 AC: 15741 AN: 152180 Hom.: 973 Cov.: 32 AF XY: 0.106 AC XY: 7861 AN XY: 74400

African (AFR) AF: 0.102 AC: 4230 AN: 41492

American (AMR) AF: 0.178 AC: 2727 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3472

East Asian (EAS) AF: 0.209 AC: 1080 AN: 5172

South Asian (SAS) AF: 0.208 AC: 1000 AN: 4816

European-Finnish (FIN) AF: 0.0553 AC: 586 AN: 10600

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0789 AC: 5367 AN: 68020

Other (OTH) AF: 0.117 AC: 248 AN: 2114

Alfa AF: 0.0917 Hom.: 387

Bravo AF: 0.110

Asia WGS AF: 0.191 AC: 665 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.23
DANN	Benign	0.52
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs2292883; hg19: chr2-238443000; COSMIC: COSV52823691;