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: 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=-0.92).
• BP6: Variant 2-237534357-C-T is Benign according to our data. Variant chr2-237534357-C-T is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLPH	NM_024101.7	c.1021-207C>T		intron_variant	Intron 8 of 15	ENST00000264605.8	NP_077006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8	c.1021-207C>T		intron_variant	Intron 8 of 15	1	NM_024101.7	ENSP00000264605.3

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;