Genetic Variant LRMDA:p.Met1? (chr10-75431726-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001305581.2(LRMDA):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000831 in 1,203,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

LRMDA
NM_001305581.2 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.18

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

oculocutaneous albinism type 7
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

LRMDA links:

ENSG00000236842 (HGNC:):

ENSG00000236842 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 166 codons. Genomic position: 76058763. Lost 0.728 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305581.2. 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.2T>A	p.Met1?	start_lost	Exon 1 of 7	NP_001292510.1	A0A087WWI0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRMDA	ENST00000611255.5	TSL:5 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 7	ENSP00000480240.1	A0A087WWI0
ENSG00000236842	ENST00000427610.1	TSL:3	n.-138A>T		upstream_gene	N/A
ENSG00000236842	ENST00000751184.1		n.-87A>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000184

AC:

AN:

54236

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.31e-7

AC:

AN:

1203918

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

586976

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25208

American (AMR)

AF:

0.00

AC:

AN:

19272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19718

East Asian (EAS)

AF:

0.00

AC:

AN:

27416

South Asian (SAS)

AF:

0.0000215

AC:

AN:

46490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3454

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

982986

Other (OTH)

AF:

0.00

AC:

AN:

48820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000706

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Benign

0.97

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.52

PhyloP100

4.2

Sift4G

Pathogenic

0.0

Vest4

0.82

MVP

0.38

ClinPred

0.85

GERP RS

3.6

PromoterAI

-0.44

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.46

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over