rs146123023

Variant names:

• chr10-75782995-TC-T
• rs146123023
• ENST00000372499.5:c.21delC

Variant summary

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

The NM_032024.5(LRMDA):​c.21delC​(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 NM_032024.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.86
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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 8 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 VariationId is 261988.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032024.5. 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
	LRMDA	NM_001305581.2	MANE Select	c.132-253012delC		intron	N/A	NP_001292510.1	A0A087WWI0
	LRMDA	NM_032024.5		c.21delC	p.Ser8AlafsTer14	frameshift	Exon 1 of 6	NP_114413.1	Q9H2I8
	LRMDA	NR_131178.2		n.86-99660delC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRMDA	ENST00000372499.5	TSL:1	c.21delC	p.Ser8AlafsTer14	frameshift	Exon 1 of 6	ENSP00000361577.1	Q9H2I8
	LRMDA	ENST00000611255.5	TSL:5 MANE Select	c.132-253012delC		intron	N/A	ENSP00000480240.1	A0A087WWI0
	LRMDA	ENST00000593699.5	TSL:1	n.86-99660delC		intron	N/A

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

GnomAD2 exomes AF: 0.00400 AC: 1003 AN: 251006 AF XY: 0.00346

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 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

African (AFR) AF: 0.0302 AC: 1010 AN: 33478

American (AMR) AF: 0.00436 AC: 195 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 417 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.00101 AC: 1127 AN: 1112000

Other (OTH) AF: 0.00551 AC: 333 AN: 60396

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

African (AFR) AF: 0.0289 AC: 1201 AN: 41562

American (AMR) AF: 0.00595 AC: 91 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68004

Other (OTH) AF: 0.0119 AC: 25 AN: 2108

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=31/169	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs146123023; hg19: chr10-77542753; COSMIC: COSV100995385;