rs587776953

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001305581.2(LRMDA):c.150dupC(p.Ala51ArgfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

LRMDA
NM_001305581.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.06

Variant links:

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]

LRMDA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-76036025-G-GC is Pathogenic according to our data. Variant chr10-76036025-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 41917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRMDA	NM_001305581.2 link	c.150dupC	p.Ala51ArgfsTer39	frameshift_variant	Exon 3 of 7	ENST00000611255.5	NP_001292510.1	A0A087WWI0
LRMDA	NM_032024.5 link	c.66dupC	p.Ala23ArgfsTer39	frameshift_variant	Exon 2 of 6		NP_114413.1	Q9H2I8
LRMDA	NR_131178.2 link	n.504dupC		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRMDA	ENST00000611255.5 link	c.150dupC	p.Ala51ArgfsTer39	frameshift_variant	Exon 3 of 7	5	NM_001305581.2	ENSP00000480240.1	A0A087WWI0
LRMDA	ENST00000372499.5 link	c.66dupC	p.Ala23ArgfsTer39	frameshift_variant	Exon 2 of 6	1		ENSP00000361577.1	Q9H2I8
LRMDA	ENST00000593699.5 link	n.504dupC		non_coding_transcript_exon_variant	Exon 4 of 8	1
LRMDA	ENST00000593817.1 link	n.111dupC		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251300

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000280

AC:

409

AN:

1461828

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

185

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000355

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000191

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000170

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oculocutaneous albinism type 7

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	The LRMDA c.66dup; p.Ala23ArgfsTer39 variant (rs587776953) is reported in the literature in several affected homozygous individuals (Bataille 2020, Gronskov 2013, Lasseaux 2018). This variant is also reported in ClinVar (Variation ID: 41917). This variant is found in the general population with an overall allele frequency of 0.007% (19/282,690 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bataille P et al. Clinical variability and probable founder effect in oculocutaneous albinism type 7. Clin Genet. 2020 Mar;97(3):527-528. PMID: 31694064. Gronskov K et al. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism. Am J Hum Genet. 2013 Mar 7;92(3):415-21. PMID: 23395477. Lasseaux E et al. Molecular characterization of a series of 990 index patients with albinism. Pigment Cell Melanoma Res. 2018 Jul;31(4):466-474. PMID: 29345414. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 07, 2013	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2024	This sequence change creates a premature translational stop signal (p.Ala23Argfs*39) in the C10orf11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C10orf11 are known to be pathogenic (PMID: 23395477, 29345414). This variant is present in population databases (rs758262905, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 23395477, 31694064). This variant is also known as c.150dupC. ClinVar contains an entry for this variant (Variation ID: 41917). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29345414, 31980526, 31694064, 23395477) -

LRMDA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

The LRMDA c.66dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala23Argfs*39). This variant has been reported in the homozygous state in individuals with autosomal recessive oculocutaneous albinism (Grønskov et al. 2013. PubMed ID: 23395477; Supplemental Table, Holtan et al. 2019. PubMed ID: 31429209; Bataille et al. 2020. PubMed ID: 31694064). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in LRMDA are expected to be pathogenic. We interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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