11-111540878-T-G

Position:

• chr11-111540878-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000375614.7(LAYN):​c.35T>G​(p.Leu12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,379,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: LAYN ENST00000375614.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

Genes affected

LAYN (HGNC:29471): (layilin) Enables hyaluronic acid binding activity. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAYN	NM_178834.5	c.35T>G	p.Leu12Arg	missense_variant	1/7	ENST00000375614.7	NP_849156.1
LAYN	NM_001258390.2	c.35T>G	p.Leu12Arg	missense_variant	1/8		NP_001245319.1
LAYN	NM_001258391.2	c.-243T>G		5_prime_UTR_variant	1/6		NP_001245320.1
LAYN	NM_001318799.1	c.-348+544T>G		intron_variant			NP_001305728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAYN	ENST00000375614.7	c.35T>G	p.Leu12Arg	missense_variant	1/7	1	NM_178834.5	ENSP00000364764	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1379938 Hom.: 0 Cov.: 30 AF XY: 0.00000294 AC XY: 2 AN XY: 680930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 33

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

Apr 25, 2022

The c.35T>G (p.L12R) alteration is located in exon 1 (coding exon 1) of the LAYN gene. This alteration results from a T to G substitution at nucleotide position 35, causing the leucine (L) at amino acid position 12 to be replaced by an arginine (R). 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	0.16
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	.;T;T;T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.042
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;M;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.24	T;D;D;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.72
MutPred		0.74		Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);
MVP		0.60
MPC		0.55
ClinPred		0.92	D
GERP RS		3.5
Varity_R		0.32
gMVP		0.78

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: rs1290458062; hg19: chr11-111411603;