18-6980524-T-C

Variant names:

• chr18-6980524-T-C
• rs607230
• NM_005559.4:c.6004A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005559.4(LAMA1):​c.6004A>G​(p.Lys2002Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,564,944 control chromosomes in the GnomAD database, including 401,658 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36221 hom., cov: 33)
  • Exomes 𝑓: 0.72 (365437 hom.)
• Consequence: LAMA1 NM_005559.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.50
• Publications: 38 publications found

Genes affected

LAMA1 (HGNC:6481): (laminin subunit alpha 1) This gene encodes one of the alpha 1 subunits of laminin. The laminins are a family of extracellular matrix glycoproteins that have a heterotrimeric structure consisting of an alpha, beta and gamma chain. These proteins make up a major component of the basement membrane and have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Mutations in this gene may be associated with Poretti-Boltshauser syndrome. [provided by RefSeq, Sep 2014]

LAMA1 Gene-Disease associations (from GenCC):

• ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.886197E-7).
• BP6: Variant 18-6980524-T-C is Benign according to our data. Variant chr18-6980524-T-C is described in ClinVar as Benign. ClinVar VariationId is 1168731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA1	NM_005559.4	c.6004A>G	p.Lys2002Glu	missense_variant	Exon 42 of 63	ENST00000389658.4	NP_005550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA1	ENST00000389658.4	c.6004A>G	p.Lys2002Glu	missense_variant	Exon 42 of 63	1	NM_005559.4	ENSP00000374309.3
LAMA1	ENST00000579014.5	n.7019A>G		non_coding_transcript_exon_variant	Exon 41 of 62	2

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104126 AN: 151996 Hom.: 36196 Cov.: 33

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.745

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.710

GnomAD2 exomes AF: 0.735 AC: 184537 AN: 251108 AF XY: 0.733

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.833

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.827

Gnomad FIN exome AF: 0.748

Gnomad NFE exome AF: 0.715

Gnomad OTH exome AF: 0.735

GnomAD4 exome AF: 0.718 AC: 1013922 AN: 1412830 Hom.: 365437 Cov.: 25 AF XY: 0.718 AC XY: 507326 AN XY: 706436

African (AFR) AF: 0.559 AC: 18196 AN: 32544

American (AMR) AF: 0.827 AC: 36929 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 18770 AN: 25838

East Asian (EAS) AF: 0.824 AC: 32508 AN: 39448

South Asian (SAS) AF: 0.726 AC: 61848 AN: 85220

European-Finnish (FIN) AF: 0.745 AC: 39698 AN: 53280

Middle Eastern (MID) AF: 0.697 AC: 3955 AN: 5674

European-Non Finnish (NFE) AF: 0.712 AC: 759811 AN: 1067458

Other (OTH) AF: 0.719 AC: 42207 AN: 58716

GnomAD4 genome AF: 0.685 AC: 104198 AN: 152114 Hom.: 36221 Cov.: 33 AF XY: 0.690 AC XY: 51300 AN XY: 74340

African (AFR) AF: 0.563 AC: 23358 AN: 41456

American (AMR) AF: 0.750 AC: 11464 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2504 AN: 3470

East Asian (EAS) AF: 0.834 AC: 4316 AN: 5176

South Asian (SAS) AF: 0.732 AC: 3535 AN: 4828

European-Finnish (FIN) AF: 0.745 AC: 7881 AN: 10580

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48906 AN: 67998

Other (OTH) AF: 0.708 AC: 1495 AN: 2112

Alfa AF: 0.710 Hom.: 190286

Bravo AF: 0.682

TwinsUK AF: 0.728 AC: 2700

ALSPAC AF: 0.697 AC: 2688

ESP6500AA AF: 0.553 AC: 2436

ESP6500EA AF: 0.715 AC: 6146

ExAC AF: 0.727 AC: 88298

Asia WGS AF: 0.788 AC: 2738 AN: 3476

EpiCase AF: 0.712

EpiControl AF: 0.719

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 08, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.5
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.97	N
REVEL	Benign	0.034
Sift	Benign	0.43	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.15
ClinPred		0.0046	T
GERP RS		3.3
Varity_R		0.039
gMVP		0.082
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs607230; hg19: chr18-6980523; COSMIC: COSV107500176;