rs753971789

Variant names:

• chr10-75782986-A-G
• rs753971789
• ENST00000372499.5:c.11A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032024.5(LRMDA):​c.11A>G​(p.Tyr4Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRMDA NM_032024.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14275992).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032024.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRMDA	NM_001305581.2	MANE Select	c.132-253022A>G		intron	N/A	NP_001292510.1	A0A087WWI0
	LRMDA	NM_032024.5		c.11A>G	p.Tyr4Cys	missense	Exon 1 of 6	NP_114413.1	Q9H2I8
	LRMDA	NR_131178.2		n.86-99670A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRMDA	ENST00000372499.5	TSL:1	c.11A>G	p.Tyr4Cys	missense	Exon 1 of 6	ENSP00000361577.1	Q9H2I8
	LRMDA	ENST00000611255.5	TSL:5 MANE Select	c.132-253022A>G		intron	N/A	ENSP00000480240.1	A0A087WWI0
	LRMDA	ENST00000593699.5	TSL:1	n.86-99670A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251014 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.0
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.067
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.063	B
Vest4		0.34
MutPred		0.31		Gain of catalytic residue at L5 (P = 0.0104)
MVP		0.46
MPC		0.17
ClinPred		0.41	T
GERP RS		5.6
PromoterAI		-0.0045	Neutral
Varity_R		0.095
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs753971789; hg19: chr10-77542744; COSMIC: COSV100995700;