2-237510979-G-A

Position:

chr2-237510979-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Variant links:

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]

MLPH links:

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]

MIR6811 links:

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ACMG classification

Classification made for transcript

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 GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLPH	NM_024101.7 linkuse as main transcript	c.333-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264605.8	NP_077006.1
MIR6811	NR_106869.1 linkuse as main transcript	n.49G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8 linkuse as main transcript	c.333-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_024101.7	ENSP00000264605	A2	Q9BV36-1
MIR6811	ENST00000620409.1 linkuse as main transcript	n.49G>A		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

938

AN:

152010

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00596

AC XY:

809

AN XY:

135776

show subpopulations

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.:

Cov.:

AF XY:

0.00425

AC XY:

3091

AN XY:

726516

show subpopulations

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.:

Cov.:

AF XY:

0.00809

AC XY:

602

AN XY:

74368

show subpopulations

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.:

Bravo

AF:

0.00205

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over