20-62309410-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_005560.6(LAMA5):c.11014C>T(p.Arg3672Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,585,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: LAMA5 NM_005560.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.459

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011445105).
• BP6: Variant 20-62309410-G-A is Benign according to our data. Variant chr20-62309410-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2164307.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA5	NM_005560.6	c.11014C>T	p.Arg3672Trp	missense_variant	80/80	ENST00000252999.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA5	ENST00000252999.7	c.11014C>T	p.Arg3672Trp	missense_variant	80/80	1	NM_005560.6	P1
LAMA5	ENST00000370691.6	n.2809C>T		non_coding_transcript_exon_variant	17/17	1
LAMA5	ENST00000495695.1	n.515C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 151966 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000190 AC: 39 AN: 205240 Hom.: 0 AF XY: 0.000177 AC XY: 20 AN XY: 113300

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.0000802 AC: 115 AN: 1433590 Hom.: 0 Cov.: 32 AF XY: 0.0000800 AC XY: 57 AN XY: 712144

Gnomad4 AFR exome AF: 0.00216

Gnomad4 AMR exome AF: 0.000375

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000840

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.000201

GnomAD4 genome AF: 0.000717 AC: 109 AN: 152084 Hom.: 0 Cov.: 30 AF XY: 0.000740 AC XY: 55 AN XY: 74340

Gnomad4 AFR AF: 0.00251

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000369 Hom.: 0

Bravo AF: 0.000918

ESP6500AA AF: 0.00119 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000186 AC: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.11014C>T (p.R3672W) alteration is located in exon 80 (coding exon 80) of the LAMA5 gene. This alteration results from a C to T substitution at nucleotide position 11014, causing the arginine (R) at amino acid position 3672 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.017	D
Polyphen		0.0090	B
Vest4		0.18
MVP		0.52
ClinPred		0.078	T
GERP RS		-0.76
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.098
gMVP		0.47

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: rs202130407; hg19: chr20-60884466;