rs11757455

Variant names:

• chr6-112201651-G-A
• rs11757455
• NM_001105206.3:c.460C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-112201651-G-A
• chr6-112201651-G-C

Variant summary

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

The NM_001105206.3(LAMA4):​c.460C>T​(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,613,122 control chromosomes in the GnomAD database, including 3,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R154R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.044 (219 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3326 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.45
• Publications: 28 publications found

Genes affected

LAMA4 (HGNC:6484): (laminin subunit alpha 4) 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. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the alpha chain isoform laminin, alpha 4. The domain structure of alpha 4 is similar to that of alpha 3, both of which resemble truncated versions of alpha 1 and alpha 2, in that approximately 1,200 residues at the N-terminus (domains IV, V and VI) have been lost. Laminin, alpha 4 contains the C-terminal G domain which distinguishes all alpha chains from the beta and gamma chains. The RNA analysis from adult and fetal tissues revealed developmental regulation of expression, however, the exact function of laminin, alpha 4 is not known. Tissue-specific utilization of alternative polyA-signal has been described in literature. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

LAMA4 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1JJ

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.006450653).
• BP6: Variant 6-112201651-G-A is Benign according to our data. Variant chr6-112201651-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105206.3. 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
	LAMA4	NM_001105206.3	MANE Select	c.460C>T	p.Arg154Trp	missense	Exon 5 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.460C>T	p.Arg154Trp	missense	Exon 5 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.460C>T	p.Arg154Trp	missense	Exon 5 of 39	NP_002281.3	Q16363-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.460C>T	p.Arg154Trp	missense	Exon 5 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.460C>T	p.Arg154Trp	missense	Exon 5 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.460C>T	p.Arg154Trp	missense	Exon 5 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 6673 AN: 152102 Hom.: 223 Cov.: 33

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0863

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0522 AC: 13101 AN: 250976 AF XY: 0.0574

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0401

Gnomad NFE exome AF: 0.0645

Gnomad OTH exome AF: 0.0542

GnomAD4 exome AF: 0.0624 AC: 91135 AN: 1460902 Hom.: 3326 Cov.: 31 AF XY: 0.0640 AC XY: 46547 AN XY: 726756

African (AFR) AF: 0.0101 AC: 337 AN: 33446

American (AMR) AF: 0.0292 AC: 1304 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 1015 AN: 26124

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39690

South Asian (SAS) AF: 0.0970 AC: 8364 AN: 86228

European-Finnish (FIN) AF: 0.0403 AC: 2154 AN: 53390

Middle Eastern (MID) AF: 0.0821 AC: 473 AN: 5764

European-Non Finnish (NFE) AF: 0.0664 AC: 73784 AN: 1111196

Other (OTH) AF: 0.0612 AC: 3693 AN: 60350

GnomAD4 genome AF: 0.0438 AC: 6666 AN: 152220 Hom.: 219 Cov.: 33 AF XY: 0.0430 AC XY: 3203 AN XY: 74424

African (AFR) AF: 0.0116 AC: 480 AN: 41540

American (AMR) AF: 0.0409 AC: 625 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0860 AC: 414 AN: 4814

European-Finnish (FIN) AF: 0.0370 AC: 392 AN: 10604

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0660 AC: 4491 AN: 68016

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0593 Hom.: 1188

Bravo AF: 0.0409

TwinsUK AF: 0.0766 AC: 284

ALSPAC AF: 0.0695 AC: 268

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0530 AC: 6440

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.0669

EpiControl AF: 0.0684

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	1	Dilated cardiomyopathy 1JJ (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0065	T
MetaSVM	Uncertain	-0.23	T
PhyloP100		2.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.48
MPC		0.58
ClinPred		0.036	T
GERP RS		4.2
gMVP		0.64
Mutation Taster		=100/0	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: rs11757455; hg19: chr6-112522852; COSMIC: COSV57898447;