rs34753919

Variant names:

• chr6-112129944-G-A
• rs34753919
• NM_001105206.3:c.4065C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-112129944-G-A
• chr6-112129944-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001105206.3(LAMA4):​c.4065C>T​(p.Phe1355Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,612,690 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: LAMA4 NM_001105206.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.640
• Publications: 1 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 6-112129944-G-A is Benign according to our data. Variant chr6-112129944-G-A is described in ClinVar as Benign. ClinVar VariationId is 44381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1614/152192) while in subpopulation AFR AF = 0.0339 (1409/41534). AF 95% confidence interval is 0.0325. There are 24 homozygotes in GnomAd4. There are 797 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1614 AD gene.

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.4065C>T	p.Phe1355Phe	synonymous	Exon 30 of 39	NP_001098676.2
	LAMA4	NM_001105207.3		c.4044C>T	p.Phe1348Phe	synonymous	Exon 30 of 39	NP_001098677.2
	LAMA4	NM_002290.5		c.4044C>T	p.Phe1348Phe	synonymous	Exon 30 of 39	NP_002281.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.4065C>T	p.Phe1355Phe	synonymous	Exon 30 of 39	ENSP00000230538.7
	LAMA4	ENST00000389463.9	TSL:1	c.4044C>T	p.Phe1348Phe	synonymous	Exon 30 of 39	ENSP00000374114.4
	LAMA4	ENST00000522006.5	TSL:1	c.4044C>T	p.Phe1348Phe	synonymous	Exon 30 of 39	ENSP00000429488.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1612 AN: 152074 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00878

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00326 AC: 816 AN: 250398 AF XY: 0.00262

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.00282

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00142 AC: 2078 AN: 1460498 Hom.: 32 Cov.: 30 AF XY: 0.00126 AC XY: 918 AN XY: 726586

African (AFR) AF: 0.0353 AC: 1181 AN: 33448

American (AMR) AF: 0.00343 AC: 153 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00590 AC: 154 AN: 26110

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39638

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5766

European-Non Finnish (NFE) AF: 0.000342 AC: 380 AN: 1111118

Other (OTH) AF: 0.00272 AC: 164 AN: 60310

GnomAD4 genome AF: 0.0106 AC: 1614 AN: 152192 Hom.: 24 Cov.: 32 AF XY: 0.0107 AC XY: 797 AN XY: 74420

African (AFR) AF: 0.0339 AC: 1409 AN: 41534

American (AMR) AF: 0.00877 AC: 134 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67990

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00528 Hom.: 7

Bravo AF: 0.0124

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000653

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Dilated cardiomyopathy 1JJ (4)
-	-	1	Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.5
DANN	Benign	0.61
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

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: rs34753919; hg19: chr6-112451146;