20-62330822-A-G

Position:

• chr20-62330822-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005560.6(LAMA5):​c.3773T>C​(p.Met1258Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.894 in 1,547,168 control chromosomes in the GnomAD database, including 625,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.80 (50275 hom., cov: 31)
  • Exomes 𝑓: 0.90 (574762 hom.)
• Consequence: LAMA5 NM_005560.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.296

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.261096E-7).
• BP6: Variant 20-62330822-A-G is Benign according to our data. Variant chr20-62330822-A-G is described in ClinVar as [Benign]. Clinvar id is 1233173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA5	NM_005560.6	c.3773T>C	p.Met1258Thr	missense_variant	30/80	ENST00000252999.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA5	ENST00000252999.7	c.3773T>C	p.Met1258Thr	missense_variant	30/80	1	NM_005560.6	P1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120941 AN: 151864 Hom.: 50268 Cov.: 31

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.948

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.852

Gnomad MID AF: 0.831

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.840

GnomAD3 exomes AF: 0.859 AC: 135333 AN: 157512 Hom.: 58994 AF XY: 0.864 AC XY: 72427 AN XY: 83786

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.818

Gnomad ASJ exome AF: 0.896

Gnomad EAS exome AF: 0.952

Gnomad SAS exome AF: 0.800

Gnomad FIN exome AF: 0.854

Gnomad NFE exome AF: 0.925

Gnomad OTH exome AF: 0.866

GnomAD4 exome AF: 0.905 AC: 1262294 AN: 1395186 Hom.: 574762 Cov.: 63 AF XY: 0.903 AC XY: 621480 AN XY: 688008

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.815

Gnomad4 ASJ exome AF: 0.899

Gnomad4 EAS exome AF: 0.953

Gnomad4 SAS exome AF: 0.802

Gnomad4 FIN exome AF: 0.852

Gnomad4 NFE exome AF: 0.929

Gnomad4 OTH exome AF: 0.884

GnomAD4 genome AF: 0.796 AC: 121000 AN: 151982 Hom.: 50275 Cov.: 31 AF XY: 0.793 AC XY: 58902 AN XY: 74282

Gnomad4 AFR AF: 0.534

Gnomad4 AMR AF: 0.803

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.942

Gnomad4 SAS AF: 0.800

Gnomad4 FIN AF: 0.852

Gnomad4 NFE AF: 0.925

Gnomad4 OTH AF: 0.841

Alfa AF: 0.886 Hom.: 18900

Bravo AF: 0.783

TwinsUK AF: 0.936 AC: 3470

ALSPAC AF: 0.927 AC: 3571

ESP6500AA AF: 0.565 AC: 2406

ESP6500EA AF: 0.929 AC: 7826

ExAC AF: 0.825 AC: 86413

Asia WGS AF: 0.837 AC: 2911 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 19435634) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.29
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.087	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.037
Sift	Benign	0.45	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.029
ClinPred		0.0027	T
GERP RS		1.8
Varity_R		0.021
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3810548; hg19: chr20-60905878; COSMIC: COSV53354046; COSMIC: COSV53354046;