rs878854351

Positions:

• chr10-76047256-C-A
• chr10-76047256-C-G
• chr10-76047256-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001305581.2(LRMDA):​c.351C>A​(p.Asn117Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRMDA NM_001305581.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0860

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-76047256-C-A is Pathogenic according to our data. Variant chr10-76047256-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209972.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRMDA	NM_001305581.2	c.351C>A	p.Asn117Lys	missense_variant	4/7	ENST00000611255.5	NP_001292510.1
LRMDA	NM_032024.5	c.267C>A	p.Asn89Lys	missense_variant	3/6		NP_114413.1
LRMDA	NR_131178.2	n.705C>A		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRMDA	ENST00000611255.5	c.351C>A	p.Asn117Lys	missense_variant	4/7	5	NM_001305581.2	ENSP00000480240.1
LRMDA	ENST00000372499.5	c.267C>A	p.Asn89Lys	missense_variant	3/6	1		ENSP00000361577.1
LRMDA	ENST00000593699.5	n.705C>A		non_coding_transcript_exon_variant	5/8	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461666 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculocutaneous albinism type 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Science and Research Branch, Islamic Azad University, Islamic Azad University

Aug 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.91	T
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		1.0	D
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.79
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854351; hg19: chr10-77807014;