7-108034216-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007356.3(LAMB4):c.4810G>A(p.Val1604Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LAMB4 NM_007356.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.86

Genes affected

LAMB4 (HGNC:6491): (laminin subunit beta 4) Predicted to be an extracellular matrix structural constituent. Predicted to be involved in several processes, including basement membrane assembly; cell migration; and substrate adhesion-dependent cell spreading. Predicted to be located in basement membrane; extracellular region; and membrane. Predicted to be part of laminin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083673894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB4	NM_007356.3	c.4810G>A	p.Val1604Met	missense_variant	31/34	ENST00000388781.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB4	ENST00000388781.8	c.4810G>A	p.Val1604Met	missense_variant	31/34	1	NM_007356.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.4810G>A (p.V1604M) alteration is located in exon 31 (coding exon 30) of the LAMB4 gene. This alteration results from a G to A substitution at nucleotide position 4810, causing the valine (V) at amino acid position 1604 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.81
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.81	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.031	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.72	P;P;.
Vest4		0.11
MutPred		0.28		Gain of ubiquitination at K1601 (P = 0.0728);Gain of ubiquitination at K1601 (P = 0.0728);.;
MVP		0.067
MPC		0.067
ClinPred		0.25	T
GERP RS		-4.7
Varity_R		0.047
gMVP		0.076

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

Publications

LitVar

Other links and lift over

dbSNP: rs2035145623; hg19: chr7-107674661;