rs139502000

Variant names:

• chr20-62310186-C-T
• rs139502000
• NM_005560.6:c.10726G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005560.6(LAMA5):​c.10726G>A​(p.Glu3576Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,612,484 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.0038 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (17 hom.)
• Consequence: LAMA5 NM_005560.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.618
• Publications: 14 publications found

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):

• LAMA5-related multisystemic syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• nephrotic syndrome, IIa 26

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006543368).
• BP6: Variant 20-62310186-C-T is Benign according to our data. Variant chr20-62310186-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438605.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00384 (585/152314) while in subpopulation NFE AF = 0.00616 (419/68010). AF 95% confidence interval is 0.00567. There are 4 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005560.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA5	NM_005560.6	MANE Select	c.10726G>A	p.Glu3576Lys	missense	Exon 77 of 80	NP_005551.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA5	ENST00000252999.7	TSL:1 MANE Select	c.10726G>A	p.Glu3576Lys	missense	Exon 77 of 80	ENSP00000252999.3	O15230-1
	LAMA5	ENST00000370691.6	TSL:1	n.2521G>A		non_coding_transcript_exon	Exon 14 of 17
	LAMA5	ENST00000495695.1	TSL:2	n.227G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152196 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00324 AC: 803 AN: 248092 AF XY: 0.00329

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00584

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00485 AC: 7083 AN: 1460170 Hom.: 17 Cov.: 49 AF XY: 0.00473 AC XY: 3438 AN XY: 726362

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00188 AC: 84 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00677 AC: 177 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86258

European-Finnish (FIN) AF: 0.00365 AC: 189 AN: 51798

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00564 AC: 6267 AN: 1111956

Other (OTH) AF: 0.00424 AC: 256 AN: 60372

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152314 Hom.: 4 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74464

African (AFR) AF: 0.00101 AC: 42 AN: 41578

American (AMR) AF: 0.00183 AC: 28 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00616 AC: 419 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00476 Hom.: 7

Bravo AF: 0.00329

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00582 AC: 50

ExAC AF: 0.00285 AC: 345

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00486

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Polymicrogyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.78
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.62
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	0.48	T
Sift4G	Benign	0.77	T
Polyphen		0.28	B
Vest4		0.13
MVP		0.38
ClinPred		0.0017	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.50
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139502000; hg19: chr20-60885242; COSMIC: COSV53362705; COSMIC: COSV53362705;