rs3751109

Positions:

• chr2-237518551-T-C

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.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. 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 0.20 (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

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=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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLPH	NM_024101.7	c.458T>C	p.Leu153Pro	missense_variant	5/16	ENST00000264605.8	NP_077006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8	c.458T>C	p.Leu153Pro	missense_variant	5/16	1	NM_024101.7	ENSP00000264605	A2

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

GnomAD3 exomes AF: 0.145 AC: 36068 AN: 248958 Hom.: 3152 AF XY: 0.142 AC XY: 19182 AN XY: 134752

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 SAS exome AF: 0.120

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

Gnomad4 AFR exome AF: 0.348

Gnomad4 AMR exome AF: 0.0770

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.0675

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.164

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

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.0724

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.171

Alfa AF: 0.164 Hom.: 4837

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.080	N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.48	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.019
MPC		0.17
ClinPred		0.00041	T
GERP RS		-2.8
Varity_R		0.040
gMVP		0.14

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: rs3751109; hg19: chr2-238427194; COSMIC: COSV52820444; COSMIC: COSV52820444;