10-76036034-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001305581.2(LRMDA):c.158G>C(p.Arg53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R53R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRMDA NM_001305581.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.114473164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRMDA	NM_001305581.2	c.158G>C	p.Arg53Thr	missense_variant	3/7	ENST00000611255.5
LRMDA	NM_032024.5	c.74G>C	p.Arg25Thr	missense_variant	2/6
LRMDA	NR_131178.2	n.512G>C		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRMDA	ENST00000611255.5	c.158G>C	p.Arg53Thr	missense_variant	3/7	5	NM_001305581.2	P1
LRMDA	ENST00000372499.5	c.74G>C	p.Arg25Thr	missense_variant	2/6	1
LRMDA	ENST00000593699.5	n.512G>C		non_coding_transcript_exon_variant	4/8	1
LRMDA	ENST00000593817.1	n.119G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 2022

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 25 of the C10orf11 protein (p.Arg25Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with C10orf11-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.66
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N;N
Sift4G	Benign	0.62	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.23
MutPred		0.38		.;Loss of phosphorylation at S22 (P = 0.114);.;
MVP		0.45
MPC		0.18
ClinPred		0.037	T
GERP RS		2.3
Varity_R		0.096
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-77795792;