rs2032567

Variant names:

• chr6-112136188-C-T
• rs2032567
• NM_001105206.3:c.3349G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-112136188-C-T
• chr6-112136188-C-G

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.3349G>A​(p.Gly1117Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 1,611,098 control chromosomes in the GnomAD database, including 440,616 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45980 hom., cov: 32)
  • Exomes 𝑓: 0.73 (394636 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.50
• Publications: 39 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

LOC107986633 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=9.803636E-7).
• BP6: Variant 6-112136188-C-T is Benign according to our data. Variant chr6-112136188-C-T is described in ClinVar as Benign. ClinVar VariationId is 44376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.852 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.3349G>A	p.Gly1117Ser	missense	Exon 25 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.3328G>A	p.Gly1110Ser	missense	Exon 25 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.3328G>A	p.Gly1110Ser	missense	Exon 25 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.3349G>A	p.Gly1117Ser	missense	Exon 25 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.3328G>A	p.Gly1110Ser	missense	Exon 25 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.3328G>A	p.Gly1110Ser	missense	Exon 25 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117540 AN: 151994 Hom.: 45922 Cov.: 32

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.758

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.764

GnomAD2 exomes AF: 0.775 AC: 194311 AN: 250840 AF XY: 0.773

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.702

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.733 AC: 1069192 AN: 1458986 Hom.: 394636 Cov.: 34 AF XY: 0.736 AC XY: 534390 AN XY: 726006

African (AFR) AF: 0.862 AC: 28819 AN: 33424

American (AMR) AF: 0.866 AC: 38695 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.758 AC: 19795 AN: 26100

East Asian (EAS) AF: 0.862 AC: 34157 AN: 39638

South Asian (SAS) AF: 0.858 AC: 74024 AN: 86228

European-Finnish (FIN) AF: 0.741 AC: 39501 AN: 53294

Middle Eastern (MID) AF: 0.708 AC: 4076 AN: 5756

European-Non Finnish (NFE) AF: 0.708 AC: 785068 AN: 1109562

Other (OTH) AF: 0.747 AC: 45057 AN: 60280

GnomAD4 genome AF: 0.774 AC: 117660 AN: 152112 Hom.: 45980 Cov.: 32 AF XY: 0.777 AC XY: 57746 AN XY: 74346

African (AFR) AF: 0.860 AC: 35684 AN: 41514

American (AMR) AF: 0.812 AC: 12411 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.758 AC: 2628 AN: 3468

East Asian (EAS) AF: 0.864 AC: 4469 AN: 5172

South Asian (SAS) AF: 0.872 AC: 4201 AN: 4820

European-Finnish (FIN) AF: 0.734 AC: 7763 AN: 10570

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.707 AC: 48022 AN: 67970

Other (OTH) AF: 0.766 AC: 1618 AN: 2112

Alfa AF: 0.732 Hom.: 174086

Bravo AF: 0.778

ESP6500AA AF: 0.858 AC: 3782

ESP6500EA AF: 0.697 AC: 5990

ExAC AF: 0.769 AC: 93360

Asia WGS AF: 0.890 AC: 3092 AN: 3478

EpiCase AF: 0.705

EpiControl AF: 0.709

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Dilated cardiomyopathy 1JJ (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.19
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.019	T
MetaRNN	Benign	9.8e-7	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	0.53	T
Vest4		0.039
MPC		0.12
ClinPred		0.0088	T
GERP RS		5.9
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2032567; hg19: chr6-112457390; COSMIC: COSV57893884;