20-62309391-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005560.6(LAMA5):c.11033C>G(p.Thr3678Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,589,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LAMA5 NM_005560.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.607

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0609712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA5	NM_005560.6	c.11033C>G	p.Thr3678Ser	missense_variant	80/80	ENST00000252999.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA5	ENST00000252999.7	c.11033C>G	p.Thr3678Ser	missense_variant	80/80	1	NM_005560.6	P1
LAMA5	ENST00000370691.6	n.2828C>G		non_coding_transcript_exon_variant	17/17	1
LAMA5	ENST00000495695.1	n.534C>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152066 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000187 AC: 4 AN: 214174 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 118414

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 SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1437728 Hom.: 0 Cov.: 32 AF XY: 0.00000979 AC XY: 7 AN XY: 714670

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.0000502

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152066 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74254

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

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: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

LAMA5-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

The LAMA5 c.11033C>G variant is predicted to result in the amino acid substitution p.Thr3678Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-60884447-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	1.4
Dann	Benign	0.39
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.74	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.12
Sift	Benign	0.46	T
Sift4G	Benign	0.85	T
Polyphen		0.0020	B
Vest4		0.035
MutPred		0.24		Gain of disorder (P = 0.0252);
MVP		0.43
ClinPred		0.030	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.32

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: rs541928558; hg19: chr20-60884447;