10-75438487-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001305581.2(LRMDA):c.124C>T(p.Leu42Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,550,516 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (4 hom.)
• Consequence: LRMDA NM_001305581.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.91

Genes affected

LRMDA (HGNC:23405): (leucine rich melanocyte differentiation associated) This gene encodes a leucine-rich repeat protein. The encoded protein is thought to play a role in melanocyte differentiation. Mutations in this gene have been associated with autosomal recessive oculocutaneous albinism 7 (OCA7). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009137273).
• BP6: Variant 10-75438487-C-T is Benign according to our data. Variant chr10-75438487-C-T is described in ClinVar as [Benign]. Clinvar id is 3034272.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0004 (61/152348) while in subpopulation EAS AF= 0.0083 (43/5180). AF 95% confidence interval is 0.00633. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRMDA	NM_001305581.2	c.124C>T	p.Leu42Phe	missense_variant	2/7	ENST00000611255.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRMDA	ENST00000611255.5	c.124C>T	p.Leu42Phe	missense_variant	2/7	5	NM_001305581.2	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00828

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000829 AC: 124 AN: 149642 Hom.: 0 AF XY: 0.000857 AC XY: 69 AN XY: 80512

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00816

Gnomad SAS exome AF: 0.00133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000923

GnomAD4 exome AF: 0.000235 AC: 328 AN: 1398168 Hom.: 4 Cov.: 30 AF XY: 0.000280 AC XY: 193 AN XY: 689626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00372

Gnomad4 SAS exome AF: 0.00167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.00100

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74502

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00830

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.000306

ExAC AF: 0.000860 AC: 18

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LRMDA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.77	N
Sift4G	Uncertain	0.050	T
Vest4		0.33
MVP		0.24
ClinPred		0.022	T
GERP RS		3.5
gMVP		0.16

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138137159; hg19: chr10-77198245;