10-76036069-C-T

Variant names:

• chr10-76036069-C-T
• rs147768808
• NM_001305581.2:c.193C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001305581.2(LRMDA):​c.193C>T​(p.Leu65Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00337 in 1,614,052 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (16 hom.)
• Consequence: LRMDA NM_001305581.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.61
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-76036069-C-T is Benign according to our data. Variant chr10-76036069-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261986.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00206 (313/152174) while in subpopulation NFE AF = 0.00404 (275/68044). AF 95% confidence interval is 0.00365. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305581.2. 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.193C>T	p.Leu65Leu	synonymous	Exon 3 of 7	NP_001292510.1	A0A087WWI0
	LRMDA	NM_032024.5		c.109C>T	p.Leu37Leu	synonymous	Exon 2 of 6	NP_114413.1	Q9H2I8
	LRMDA	NR_131178.2		n.547C>T		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRMDA	ENST00000611255.5	TSL:5 MANE Select	c.193C>T	p.Leu65Leu	synonymous	Exon 3 of 7	ENSP00000480240.1	A0A087WWI0
	LRMDA	ENST00000372499.5	TSL:1	c.109C>T	p.Leu37Leu	synonymous	Exon 2 of 6	ENSP00000361577.1	Q9H2I8
	LRMDA	ENST00000593699.5	TSL:1	n.547C>T		non_coding_transcript_exon	Exon 4 of 8

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00190 AC: 477 AN: 251450 AF XY: 0.00183

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00351 AC: 5134 AN: 1461878 Hom.: 16 Cov.: 32 AF XY: 0.00342 AC XY: 2485 AN XY: 727238

African (AFR) AF: 0.000687 AC: 23 AN: 33478

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.00436 AC: 4852 AN: 1112006

Other (OTH) AF: 0.00310 AC: 187 AN: 60396

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152174 Hom.: 0 Cov.: 31 AF XY: 0.00172 AC XY: 128 AN XY: 74332

African (AFR) AF: 0.000772 AC: 32 AN: 41426

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00205

EpiCase AF: 0.00485

EpiControl AF: 0.00385

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Oculocutaneous albinism type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		5.6
PromoterAI		-0.0094	Neutral
Mutation Taster		=12/88	disease causing

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: rs147768808; hg19: chr10-77795827;