2-237493529-C-A

Variant names:

• chr2-237493529-C-A
• rs119473031
• NM_024101.7:c.103C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_024101.7(MLPH):​c.103C>A​(p.Arg35Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLPH NM_024101.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• Griscelli syndrome type 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=0.06 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024101.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	NM_024101.7	MANE Select	c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 16	NP_077006.1	Q9BV36-1
	MLPH	NM_001042467.3		c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 15	NP_001035932.1	Q9BV36-2
	MLPH	NM_001281473.2		c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 13	NP_001268402.1	Q9BV36-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	ENST00000264605.8	TSL:1 MANE Select	c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 16	ENSP00000264605.3	Q9BV36-1
	MLPH	ENST00000338530.8	TSL:1	c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 15	ENSP00000341845.4	Q9BV36-2
	MLPH	ENST00000409373.5	TSL:1	c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 13	ENSP00000386780.1	Q9BV36-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460644 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726680

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111038

Other (OTH) AF: 0.00 AC: 0 AN: 60302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.9
DANN	Benign	0.69
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs119473031; hg19: chr2-238402172;