rs2292884

Positions:

• chr2-237534583-A-G
• chr2-237534583-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024101.7(MLPH):​c.1040A>G​(p.His347Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,611,710 control chromosomes in the GnomAD database, including 64,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (10381 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54282 hom.)
• Consequence: MLPH NM_024101.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.196

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.148294E-5).
• BP6: Variant 2-237534583-A-G is Benign according to our data. Variant chr2-237534583-A-G is described in ClinVar as [Benign]. Clinvar id is 1229855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237534583-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLPH	NM_024101.7	c.1040A>G	p.His347Arg	missense_variant	9/16	ENST00000264605.8	NP_077006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8	c.1040A>G	p.His347Arg	missense_variant	9/16	1	NM_024101.7	ENSP00000264605	A2

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51597 AN: 151856 Hom.: 10354 Cov.: 32

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.284 AC: 71311 AN: 251392 Hom.: 11179 AF XY: 0.279 AC XY: 37960 AN XY: 135860

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.265 AC: 387415 AN: 1459736 Hom.: 54282 Cov.: 33 AF XY: 0.267 AC XY: 193562 AN XY: 726300

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.265

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.340 AC: 51678 AN: 151974 Hom.: 10381 Cov.: 32 AF XY: 0.336 AC XY: 24933 AN XY: 74282

Gnomad4 AFR AF: 0.565

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.341

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.245

Gnomad4 OTH AF: 0.319

Alfa AF: 0.264 Hom.: 14138

Bravo AF: 0.356

TwinsUK AF: 0.257 AC: 954

ALSPAC AF: 0.256 AC: 987

ESP6500AA AF: 0.568 AC: 2503

ESP6500EA AF: 0.255 AC: 2189

ExAC AF: 0.289 AC: 35088

Asia WGS AF: 0.302 AC: 1050 AN: 3478

EpiCase AF: 0.242

EpiControl AF: 0.244

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 21743057) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.044
DANN	Benign	0.16
DEOGEN2	Benign	0.081	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.000011	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.0	N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.82	N;N
REVEL	Benign	0.036
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.026
MPC		0.13
ClinPred		0.00098	T
GERP RS		0.013
Varity_R		0.030
gMVP		0.080

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292884; hg19: chr2-238443226; COSMIC: COSV52817878;