chr2-237518608-G-A

Position:

• chr2-237518608-G-A

Variant summary

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

The ENST00000264605.8(MLPH):​c.515G>A​(p.Gly172Asp) 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 1,612,806 control chromosomes in the GnomAD database, including 24,375 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 (3734 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20641 hom.)
• Consequence: MLPH ENST00000264605.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.131

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=0.003818363).
• BP6: Variant 2-237518608-G-A is Benign according to our data. Variant chr2-237518608-G-A is described in ClinVar as [Benign]. Clinvar id is 1224701.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.515G>A	p.Gly172Asp	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.515G>A	p.Gly172Asp	missense_variant	5/16	1	NM_024101.7	ENSP00000264605	A2

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30425 AN: 151932 Hom.: 3721 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0723

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: 36287 AN: 249978 Hom.: 3202 AF XY: 0.143 AC XY: 19320 AN XY: 135388

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.0718

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0678

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.163 AC: 237399 AN: 1460756 Hom.: 20641 Cov.: 32 AF XY: 0.161 AC XY: 117189 AN XY: 726692

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.0769

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.0675

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.200 AC: 30472 AN: 152050 Hom.: 3734 Cov.: 32 AF XY: 0.196 AC XY: 14600 AN XY: 74336

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.0720

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.171

Alfa AF: 0.166 Hom.: 4626

Bravo AF: 0.205

TwinsUK AF: 0.167 AC: 621

ALSPAC AF: 0.176 AC: 680

ESP6500AA AF: 0.347 AC: 1527

ESP6500EA AF: 0.170 AC: 1458

ExAC AF: 0.151 AC: 18377

Asia WGS AF: 0.106 AC: 369 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.155

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	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.14
DANN	Benign	0.10
DEOGEN2	Benign	0.087	.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.12	T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.12	N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.095
MPC		0.13
ClinPred		0.0011	T
GERP RS		1.5
Varity_R		0.030
gMVP		0.082

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: rs3751107; hg19: chr2-238427251; COSMIC: COSV52820461; COSMIC: COSV52820461;