2-237518551-T-C

Variant names:

• chr2-237518551-T-C
• rs3751109
• NM_024101.7:c.458T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024101.7(MLPH):​c.458T>C​(p.Leu153Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,611,472 control chromosomes in the GnomAD database, including 24,326 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3729 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20597 hom.)
• Consequence: MLPH NM_024101.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.671
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018135309).
• BP6: Variant 2-237518551-T-C is Benign according to our data. Variant chr2-237518551-T-C is described in ClinVar as Benign. ClinVar VariationId is 1267164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 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.458T>C	p.Leu153Pro	missense	Exon 5 of 16	NP_077006.1
	MLPH	NM_001042467.3		c.458T>C	p.Leu153Pro	missense	Exon 5 of 15	NP_001035932.1
	MLPH	NM_001281473.2		c.458T>C	p.Leu153Pro	missense	Exon 5 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.458T>C	p.Leu153Pro	missense	Exon 5 of 16	ENSP00000264605.3
	MLPH	ENST00000338530.8	TSL:1	c.458T>C	p.Leu153Pro	missense	Exon 5 of 15	ENSP00000341845.4
	MLPH	ENST00000409373.5	TSL:1	c.458T>C	p.Leu153Pro	missense	Exon 5 of 13	ENSP00000386780.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30399 AN: 151866 Hom.: 3715 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0726

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.145 AC: 36068 AN: 248958 AF XY: 0.142

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0718

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0676

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.162 AC: 236876 AN: 1459486 Hom.: 20597 Cov.: 32 AF XY: 0.161 AC XY: 116931 AN XY: 726030

African (AFR) AF: 0.348 AC: 11642 AN: 33414

American (AMR) AF: 0.0770 AC: 3432 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3436 AN: 26112

East Asian (EAS) AF: 0.0675 AC: 2680 AN: 39690

South Asian (SAS) AF: 0.125 AC: 10727 AN: 86048

European-Finnish (FIN) AF: 0.141 AC: 7517 AN: 53360

Middle Eastern (MID) AF: 0.110 AC: 636 AN: 5762

European-Non Finnish (NFE) AF: 0.168 AC: 186886 AN: 1110188

Other (OTH) AF: 0.164 AC: 9920 AN: 60314

GnomAD4 genome AF: 0.200 AC: 30448 AN: 151986 Hom.: 3729 Cov.: 32 AF XY: 0.196 AC XY: 14588 AN XY: 74330

African (AFR) AF: 0.342 AC: 14130 AN: 41372

American (AMR) AF: 0.113 AC: 1721 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3472

East Asian (EAS) AF: 0.0724 AC: 375 AN: 5180

South Asian (SAS) AF: 0.117 AC: 566 AN: 4826

European-Finnish (FIN) AF: 0.136 AC: 1445 AN: 10594

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11244 AN: 67952

Other (OTH) AF: 0.171 AC: 361 AN: 2112

Alfa AF: 0.170 Hom.: 10665

Bravo AF: 0.205

TwinsUK AF: 0.167 AC: 618

ALSPAC AF: 0.176 AC: 678

ESP6500AA AF: 0.346 AC: 1523

ESP6500EA AF: 0.169 AC: 1456

ExAC AF: 0.151 AC: 18298

Asia WGS AF: 0.106 AC: 370 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.64
DANN	Benign	0.20
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.67
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.071
Sift	Benign	0.48	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.17
ClinPred		0.00041	T
GERP RS		-2.8
Varity_R		0.040
gMVP		0.14
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: rs3751109; hg19: chr2-238427194; COSMIC: COSV52820444; COSMIC: COSV52820444;