20-62309346-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_005560.6(LAMA5):c.11078C>T(p.Pro3693Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,591,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: LAMA5 NM_005560.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.25

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09229335).
• BP6: Variant 20-62309346-G-A is Benign according to our data. Variant chr20-62309346-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2061071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA5	NM_005560.6	c.11078C>T	p.Pro3693Leu	missense_variant	80/80	ENST00000252999.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA5	ENST00000252999.7	c.11078C>T	p.Pro3693Leu	missense_variant	80/80	1	NM_005560.6	P1
LAMA5	ENST00000370691.6	n.2873C>T		non_coding_transcript_exon_variant	17/17	1
LAMA5	ENST00000495695.1	n.579C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151968 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000297 AC: 65 AN: 218526 Hom.: 0 AF XY: 0.000280 AC XY: 34 AN XY: 121324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00423

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000216 AC: 311 AN: 1439138 Hom.: 0 Cov.: 32 AF XY: 0.000235 AC XY: 168 AN XY: 715680

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000335

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151968 Hom.: 0 Cov.: 30 AF XY: 0.0000943 AC XY: 7 AN XY: 74194

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000259 AC: 2

ExAC AF: 0.000257 AC: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LAMA5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.092	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.83
ClinPred		0.79	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs368660251; hg19: chr20-60884402;