dbSNP rs2427283: LAMA5:p.Val1900Leu (chr20-62324150-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005560.6(LAMA5):c.5698G>T(p.Val1900Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1900M) has been classified as Benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LAMA5
NM_005560.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.328

Publications

0 publications found

Variant links:

Genes affected

LAMA5 (HGNC:6485): (laminin subunit alpha 5) This gene encodes one of the vertebrate laminin alpha chains. Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. The protein encoded by this gene is the alpha-5 subunit of of laminin-10 (laminin-511), laminin-11 (laminin-521) and laminin-15 (laminin-523). [provided by RefSeq, Jun 2013]

LAMA5 Gene-Disease associations (from GenCC):

nephrotic syndrome, IIa 26
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
LAMA5-related multisystemic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LAMA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.0812566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA5	NM_005560.6 link	c.5698G>T	p.Val1900Leu	missense_variant	Exon 43 of 80	ENST00000252999.7	NP_005551.3	O15230-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA5	ENST00000252999.7 link	c.5698G>T	p.Val1900Leu	missense_variant	Exon 43 of 80	1	NM_005560.6	ENSP00000252999.3		O15230-1
LAMA5	ENST00000464134.1 link	n.486G>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1407214

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

698644

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30266

American (AMR)

AF:

0.00

AC:

AN:

28930

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23372

East Asian (EAS)

AF:

0.00

AC:

AN:

38478

South Asian (SAS)

AF:

0.0000128

AC:

AN:

78060

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093228

Other (OTH)

AF:

0.00

AC:

AN:

57912

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.6

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.033

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.37

M_CAP

Benign

0.038

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

PhyloP100

0.33

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

REVEL

Benign

0.12

Sift

Benign

0.54

Sift4G

Benign

0.26

Polyphen

0.015

Vest4

0.14

MutPred

0.42

Loss of glycosylation at S1901 (P = 0.119);

MVP

0.75

ClinPred

0.061

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.032

gMVP

0.12

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over