20-62318579-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005560.6(LAMA5):c.7114G>A(p.Asp2372Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,610,634 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.0058 (6 hom., cov: 30)
  • Exomes 𝑓: 0.0076 (50 hom.)
• Consequence: LAMA5 NM_005560.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.462

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033178926).
• BP6: Variant 20-62318579-C-T is Benign according to our data. Variant chr20-62318579-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00583 (885/151816) while in subpopulation NFE AF= 0.00842 (572/67898). AF 95% confidence interval is 0.00785. There are 6 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA5	NM_005560.6	c.7114G>A	p.Asp2372Asn	missense_variant	53/80	ENST00000252999.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA5	ENST00000252999.7	c.7114G>A	p.Asp2372Asn	missense_variant	53/80	1	NM_005560.6	P1
LAMA5	ENST00000481120.1	n.342G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 883 AN: 151700 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00447

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00972

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00842

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00684 AC: 1692 AN: 247502 Hom.: 6 AF XY: 0.00697 AC XY: 939 AN XY: 134738

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00972

Gnomad OTH exome AF: 0.00679

GnomAD4 exome AF: 0.00756 AC: 11027 AN: 1458818 Hom.: 50 Cov.: 33 AF XY: 0.00752 AC XY: 5459 AN XY: 725742

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00832

Gnomad4 OTH exome AF: 0.00675

GnomAD4 genome AF: 0.00583 AC: 885 AN: 151816 Hom.: 6 Cov.: 30 AF XY: 0.00573 AC XY: 425 AN XY: 74182

Gnomad4 AFR AF: 0.00155

Gnomad4 AMR AF: 0.00446

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00972

Gnomad4 NFE AF: 0.00842

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00668 Hom.: 15

Bravo AF: 0.00538

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00229 AC: 10

ESP6500EA AF: 0.00924 AC: 79

ExAC AF: 0.00685 AC: 824

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LAMA5: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Polymicrogyria Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 01, 2017

this variant was indentified in an individual with malformations of cortical development -

LAMA5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.0
Dann	Benign	0.96
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.053
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.26	B
Vest4		0.17
MVP		0.33
ClinPred		0.0078	T
GERP RS		2.9
Varity_R		0.044
gMVP		0.25

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: rs111653839; hg19: chr20-60893635; COSMIC: COSV99055677; COSMIC: COSV99055677;