Genetic Variant LAMA5:p.Asp2372His (chr20-62318579-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_005560.6(LAMA5):c.7114G>C(p.Asp2372His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D2372N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LAMA5
NM_005560.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.462

Publications

7 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA5	NM_005560.6 link	c.7114G>C	p.Asp2372His	missense_variant	Exon 53 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.7114G>C	p.Asp2372His	missense_variant	Exon 53 of 80	1	NM_005560.6	ENSP00000252999.3		O15230-1
LAMA5	ENST00000481120.1 link	n.342G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111156

Other (OTH)

AF:

0.00

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.060

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.49

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

0.46

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.025

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0040

Polyphen

0.97

Vest4

0.39

MutPred

0.56

Gain of MoRF binding (P = 0.0518);

MVP

0.38

ClinPred

0.71

GERP RS

2.9

Varity_R

0.17

gMVP

0.42

Mutation Taster

=94/6

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