10-76036069-C-T

Position:

• chr10-76036069-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001305581.2(LRMDA):​c.193C>T​(p.Leu65=) 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

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 -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 id is 261986.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr10-76036069-C-T is described in Lovd as [Benign]. Variant chr10-76036069-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRMDA	NM_001305581.2	c.193C>T	p.Leu65=	synonymous_variant	3/7	ENST00000611255.5
LRMDA	NM_032024.5	c.109C>T	p.Leu37=	synonymous_variant	2/6
LRMDA	NR_131178.2	n.547C>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRMDA	ENST00000611255.5	c.193C>T	p.Leu65=	synonymous_variant	3/7	5	NM_001305581.2	P1
LRMDA	ENST00000372499.5	c.109C>T	p.Leu37=	synonymous_variant	2/6	1
LRMDA	ENST00000593699.5	n.547C>T		non_coding_transcript_exon_variant	4/8	1
LRMDA	ENST00000593817.1	n.154C>T		non_coding_transcript_exon_variant	2/2	3

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

GnomAD3 exomes AF: 0.00190 AC: 477 AN: 251450 Hom.: 1 AF XY: 0.00183 AC XY: 248 AN XY: 135888

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00310

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

Gnomad4 AFR AF: 0.000772

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00404

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00205

EpiCase AF: 0.00485

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	LRMDA: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Oculocutaneous albinism type 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Jun 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs147768808; hg19: chr10-77795827;