Variant 10-76047256-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1PM2

The NM_001305581.2(LRMDA):c.351C>G(p.Asn117Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. N117N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LRMDA
NM_001305581.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0860

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS1

Transcript NM_001305581.2 (LRMDA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 209972

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRMDA	NM_001305581.2 linkuse as main transcript	c.351C>G	p.Asn117Lys	missense_variant	4/7	ENST00000611255.5
LRMDA	NM_032024.5 linkuse as main transcript	c.267C>G	p.Asn89Lys	missense_variant	3/6
LRMDA	NR_131178.2 linkuse as main transcript	n.705C>G		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LRMDA	ENST00000611255.5 linkuse as main transcript	c.351C>G	p.Asn117Lys	missense_variant	4/7	5	NM_001305581.2	P1
LRMDA	ENST00000372499.5 linkuse as main transcript	c.267C>G	p.Asn89Lys	missense_variant	3/6	1
LRMDA	ENST00000593699.5 linkuse as main transcript	n.705C>G		non_coding_transcript_exon_variant	5/8	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This missense change has been observed in individual(s) with ocular albinism (PMID: 26818737). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 89 of the C10orf11 protein (p.Asn89Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

.;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Benign

-0.91

MutationTaster

Benign

0.94

D;D

PROVEAN

Pathogenic

-5.1

.;D;.

REVEL

Benign

0.24

Sift

Benign

0.047

.;D;.

Sift4G

Benign

0.065

T;T;D

Polyphen

1.0

.;D;.

Vest4

0.73

MutPred

0.57

.;Gain of ubiquitination at N89 (P = 0.0185);.;

MVP

0.52

MPC

0.27

ClinPred

0.99

GERP RS

-5.8

Varity_R

0.79

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over