rs1050348

Variant names:

• chr6-112172670-A-G
• rs1050348
• NM_001105206.3:c.1492T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-112172670-A-G
• chr6-112172670-A-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.1492T>C​(p.Tyr498His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,613,178 control chromosomes in the GnomAD database, including 318,947 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34350 hom., cov: 31)
  • Exomes 𝑓: 0.62 (284597 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.85
• Publications: 45 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=7.1718637E-7).
• BP6: Variant 6-112172670-A-G is Benign according to our data. Variant chr6-112172670-A-G is described in ClinVar as Benign. ClinVar VariationId is 44348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 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.1492T>C	p.Tyr498His	missense	Exon 12 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.1471T>C	p.Tyr491His	missense	Exon 12 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.1471T>C	p.Tyr491His	missense	Exon 12 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.1492T>C	p.Tyr498His	missense	Exon 12 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.1471T>C	p.Tyr491His	missense	Exon 12 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.1471T>C	p.Tyr491His	missense	Exon 12 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101220 AN: 151746 Hom.: 34306 Cov.: 31

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.705

GnomAD2 exomes AF: 0.665 AC: 167057 AN: 251280 AF XY: 0.667

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.714

Gnomad ASJ exome AF: 0.676

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.597

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.620 AC: 905871 AN: 1461314 Hom.: 284597 Cov.: 53 AF XY: 0.626 AC XY: 454790 AN XY: 726974

African (AFR) AF: 0.760 AC: 25442 AN: 33466

American (AMR) AF: 0.715 AC: 31967 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 17592 AN: 26132

East Asian (EAS) AF: 0.844 AC: 33519 AN: 39696

South Asian (SAS) AF: 0.786 AC: 67763 AN: 86234

European-Finnish (FIN) AF: 0.566 AC: 30205 AN: 53408

Middle Eastern (MID) AF: 0.699 AC: 3838 AN: 5494

European-Non Finnish (NFE) AF: 0.590 AC: 656073 AN: 1111810

Other (OTH) AF: 0.654 AC: 39472 AN: 60350

GnomAD4 genome AF: 0.667 AC: 101322 AN: 151864 Hom.: 34350 Cov.: 31 AF XY: 0.669 AC XY: 49672 AN XY: 74206

African (AFR) AF: 0.752 AC: 31133 AN: 41406

American (AMR) AF: 0.713 AC: 10886 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2365 AN: 3472

East Asian (EAS) AF: 0.830 AC: 4278 AN: 5154

South Asian (SAS) AF: 0.786 AC: 3773 AN: 4800

European-Finnish (FIN) AF: 0.554 AC: 5823 AN: 10520

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40686 AN: 67932

Other (OTH) AF: 0.708 AC: 1492 AN: 2108

Alfa AF: 0.634 Hom.: 98042

Bravo AF: 0.678

TwinsUK AF: 0.597 AC: 2212

ALSPAC AF: 0.595 AC: 2293

ESP6500AA AF: 0.740 AC: 3261

ESP6500EA AF: 0.602 AC: 5177

ExAC AF: 0.665 AC: 80709

Asia WGS AF: 0.794 AC: 2759 AN: 3478

EpiCase AF: 0.609

EpiControl AF: 0.618

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Dilated cardiomyopathy 1JJ (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	19
DANN	Benign	0.12
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.053	T
MetaRNN	Benign	7.2e-7	T
MetaSVM	Benign	-0.90	T
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.057
Sift	Benign	0.67	T
Sift4G	Benign	0.45	T
Vest4		0.040
MPC		0.16
ClinPred		0.0012	T
GERP RS		4.6
gMVP		0.18
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: rs1050348; hg19: chr6-112493872; COSMIC: COSV57902338;