rs12465081

Variant names:

• chr2-237493141-A-G
• rs12465081
• NM_024101.7:c.-24-262A>G

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.-24-262A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 152,152 control chromosomes in the GnomAD database, including 17,403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.41 (17403 hom., cov: 32)
• Consequence: MLPH NM_024101.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0600
• Publications: 9 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=-0.93).
• BP6: Variant 2-237493141-A-G is Benign according to our data. Variant chr2-237493141-A-G is described in ClinVar as Benign. ClinVar VariationId is 1230963.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.797 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.-24-262A>G		intron	N/A	NP_077006.1	Q9BV36-1
	MLPH	NM_001042467.3		c.-24-262A>G		intron	N/A	NP_001035932.1	Q9BV36-2
	MLPH	NM_001281473.2		c.-24-262A>G		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.-24-262A>G		intron	N/A	ENSP00000264605.3	Q9BV36-1
	MLPH	ENST00000338530.8	TSL:1	c.-24-262A>G		intron	N/A	ENSP00000341845.4	Q9BV36-2
	MLPH	ENST00000409373.5	TSL:1	c.-24-262A>G		intron	N/A	ENSP00000386780.1	Q9BV36-3

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61750 AN: 152034 Hom.: 17351 Cov.: 32

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.366

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

GnomAD4 genome AF: 0.407 AC: 61862 AN: 152152 Hom.: 17403 Cov.: 32 AF XY: 0.399 AC XY: 29687 AN XY: 74406

African (AFR) AF: 0.804 AC: 33352 AN: 41480

American (AMR) AF: 0.351 AC: 5370 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3472

East Asian (EAS) AF: 0.265 AC: 1374 AN: 5178

South Asian (SAS) AF: 0.377 AC: 1817 AN: 4816

European-Finnish (FIN) AF: 0.148 AC: 1572 AN: 10606

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16578 AN: 67986

Other (OTH) AF: 0.368 AC: 775 AN: 2108

Alfa AF: 0.278 Hom.: 3502

Bravo AF: 0.437

Asia WGS AF: 0.362 AC: 1260 AN: 3478

ClinVar

ClinVar submissions

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	-0.93
CADD	Benign	4.0
DANN	Benign	0.62
PhyloP100		-0.060
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: rs12465081; hg19: chr2-238401784;