10-75783000-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000372499.5(LRMDA):c.25G>A(p.Gly9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: LRMDA ENST00000372499.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.892

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0673455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRMDA	NM_001305581.2	c.132-253008G>A		intron_variant		ENST00000611255.5
LRMDA	NM_032024.5	c.25G>A	p.Gly9Ser	missense_variant	1/6
LRMDA	NR_131178.2	n.86-99656G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRMDA	ENST00000372499.5	c.25G>A	p.Gly9Ser	missense_variant	1/6	1
LRMDA	ENST00000611255.5	c.132-253008G>A		intron_variant		5	NM_001305581.2	P1
LRMDA	ENST00000593699.5	n.86-99656G>A		intron_variant, non_coding_transcript_variant		1
LRMDA	ENST00000593817.1	n.92+181669G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 250988 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135680

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000116

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: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74298

Gnomad4 AFR AF: 0.0000241

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: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000330 AC: 4

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 20, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 9 of the C10orf11 protein (p.Gly9Ser). This variant is present in population databases (rs745930126, gnomAD 0.01%). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Benign	0.00068	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	0.68	N
REVEL	Benign	0.038
Sift	Benign	0.43	T
Sift4G	Benign	0.17	T
Polyphen		0.0030	B
Vest4		0.084
MVP		0.46
MPC		0.12
ClinPred		0.035	T
GERP RS		0.74
Varity_R		0.034

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs745930126; hg19: chr10-77542758;