2-237510979-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024101.7(MLPH):c.333-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,612,280 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (70 hom.)
• Consequence: MLPH NM_024101.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002759
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -2.39

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-237510979-G-A is Benign according to our data. Variant chr2-237510979-G-A is described in ClinVar as [Benign]. Clinvar id is 744408.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-237510979-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00617 (938/152128) while in subpopulation NFE AF= 0.00485 (330/67986). AF 95% confidence interval is 0.00442. There are 21 homozygotes in gnomad4. There are 602 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLPH	NM_024101.7	c.333-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264605.8
MIR6811	NR_106869.1	n.49G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLPH	ENST00000264605.8	c.333-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_024101.7	A2
MIR6811	ENST00000620409.1	n.49G>A		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 938 AN: 152010 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00622 AC: 1562 AN: 251232 Hom.: 30 AF XY: 0.00596 AC XY: 809 AN XY: 135776

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00439 AC: 6410 AN: 1460152 Hom.: 70 Cov.: 32 AF XY: 0.00425 AC XY: 3091 AN XY: 726516

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0449

Gnomad4 NFE exome AF: 0.00332

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.00617 AC: 938 AN: 152128 Hom.: 21 Cov.: 32 AF XY: 0.00809 AC XY: 602 AN XY: 74368

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0539

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00478 Hom.: 2

Bravo AF: 0.00205

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.0060
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0040
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: rs192641134; hg19: chr2-238419622;