rs2292879

Variant names:

• chr2-237510968-A-G
• rs2292879
• NM_024101.7:c.333-21A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-237510968-A-G
• chr2-237510968-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.333-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,602,358 control chromosomes in the GnomAD database, including 57,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.33 (9978 hom., cov: 31)
  • Exomes 𝑓: 0.25 (47820 hom.)
• Consequence: MLPH NM_024101.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0680

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]

MIR6811 (HGNC:49944): (microRNA 6811) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-237510968-A-G is Benign according to our data. Variant chr2-237510968-A-G is described in ClinVar as [Benign]. Clinvar id is 1275303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLPH	NM_024101.7	c.333-21A>G		intron_variant	Intron 3 of 15	ENST00000264605.8	NP_077006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8	c.333-21A>G		intron_variant	Intron 3 of 15	1	NM_024101.7	ENSP00000264605.3

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49651 AN: 151392 Hom.: 9939 Cov.: 31

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.298

GnomAD3 exomes AF: 0.274 AC: 68892 AN: 251122 Hom.: 10623 AF XY: 0.269 AC XY: 36450 AN XY: 135734

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.300

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.248 AC: 360085 AN: 1450848 Hom.: 47820 Cov.: 31 AF XY: 0.249 AC XY: 179954 AN XY: 722338

Gnomad4 AFR exome AF: 0.577

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.285

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.328 AC: 49754 AN: 151510 Hom.: 9978 Cov.: 31 AF XY: 0.324 AC XY: 23977 AN XY: 74012

Gnomad4 AFR AF: 0.566

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.301

Alfa AF: 0.247 Hom.: 2003

Bravo AF: 0.346

Asia WGS AF: 0.339 AC: 1184 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Griscelli syndrome type 3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

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	-0.91
CADD	Benign	2.7
DANN	Benign	0.28
La Branchor		0.70
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2292879; hg19: chr2-238419611; COSMIC: COSV52819040; COSMIC: COSV52819040;