rs146123023

chr10-75782995-TC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PVS1_Strong BP6 BS1 BS2

The ENST00000372499.5(LRMDA):c.21del(p.Ser8AlafsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.00287 in 1,614,100 control chromosomes in the GnomAD database, including 63 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0097 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (43 hom.)
• Consequence: LRMDA ENST00000372499.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.86

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 Likely_benign. Variant got -5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• BP6: Variant 10-75782995-TC-T is Benign according to our data. Variant chr10-75782995-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261988.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00974 (1483/152258) while in subpopulation AFR AF= 0.0289 (1201/41562). AF 95% confidence interval is 0.0275. There are 20 homozygotes in gnomad4. There are 697 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRMDA	NM_001305581.2	c.132-253012del		intron_variant		ENST00000611255.5
LRMDA	NM_032024.5	c.21del	p.Ser8AlafsTer14	frameshift_variant	1/6
LRMDA	NR_131178.2	n.86-99660del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRMDA	ENST00000372499.5	c.21del	p.Ser8AlafsTer14	frameshift_variant	1/6	1
LRMDA	ENST00000611255.5	c.132-253012del		intron_variant		5	NM_001305581.2	P1
LRMDA	ENST00000593699.5	n.86-99660del		intron_variant, non_coding_transcript_variant		1
LRMDA	ENST00000593817.1	n.92+181665del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00975 AC: 1483 AN: 152140 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00400 AC: 1003 AN: 251006 Hom.: 11 AF XY: 0.00346 AC XY: 469 AN XY: 135690

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00216 AC: 3152 AN: 1461842 Hom.: 43 Cov.: 32 AF XY: 0.00210 AC XY: 1525 AN XY: 727216

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.00974 AC: 1483 AN: 152258 Hom.: 20 Cov.: 32 AF XY: 0.00936 AC XY: 697 AN XY: 74438

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.000830 Hom.: 2

Bravo AF: 0.0119

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	LRMDA: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs146123023; hg19: chr10-77542753; COSMIC: COSV100995385;