rs11891426

Variant names:

• chr2-237526059-T-G
• rs11891426
• NM_024101.7:c.880+254T>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.880+254T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 152,072 control chromosomes in the GnomAD database, including 9,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.30 (9507 hom., cov: 33)
• Consequence: MLPH NM_024101.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.96
• Publications: 6 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-237526059-T-G is Benign according to our data. Variant chr2-237526059-T-G is described in ClinVar as Benign. ClinVar VariationId is 1233750.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	NM_024101.7	MANE Select	c.880+254T>G		intron	N/A	NP_077006.1
	MLPH	NM_001042467.3		c.880+254T>G		intron	N/A	NP_001035932.1
	MLPH	NM_001281473.2		c.760+254T>G		intron	N/A	NP_001268402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	ENST00000264605.8	TSL:1 MANE Select	c.880+254T>G		intron	N/A	ENSP00000264605.3
	MLPH	ENST00000338530.8	TSL:1	c.880+254T>G		intron	N/A	ENSP00000341845.4
	MLPH	ENST00000409373.5	TSL:1	c.760+254T>G		intron	N/A	ENSP00000386780.1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44953 AN: 151954 Hom.: 9465 Cov.: 33

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.296 AC: 45044 AN: 152072 Hom.: 9507 Cov.: 33 AF XY: 0.291 AC XY: 21612 AN XY: 74334

African (AFR) AF: 0.603 AC: 24977 AN: 41450

American (AMR) AF: 0.168 AC: 2571 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 469 AN: 3468

East Asian (EAS) AF: 0.198 AC: 1016 AN: 5142

South Asian (SAS) AF: 0.212 AC: 1021 AN: 4824

European-Finnish (FIN) AF: 0.162 AC: 1722 AN: 10604

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.184 AC: 12509 AN: 67970

Other (OTH) AF: 0.255 AC: 540 AN: 2114

Alfa AF: 0.243 Hom.: 882

Bravo AF: 0.309

Asia WGS AF: 0.241 AC: 838 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	-0.90
CADD	Benign	0.15
DANN	Benign	0.53
PhyloP100		-6.0
PromoterAI		0.0098	Neutral
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: rs11891426; hg19: chr2-238434702;