11-10563963-G-T

Position:

• chr11-10563963-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006691.4(LYVE1):​c.374C>A​(p.Ala125Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYVE1 NM_006691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.97

Genes affected

LYVE1 (HGNC:14687): (lymphatic vessel endothelial hyaluronan receptor 1) This gene encodes a type I integral membrane glycoprotein. The encoded protein acts as a receptor and binds to both soluble and immobilized hyaluronan. This protein may function in lymphatic hyaluronan transport and have a role in tumor metastasis. [provided by RefSeq, Jul 2008]

IRAG1-AS1 (HGNC:43434): (IRAG1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053865463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYVE1	NM_006691.4	c.374C>A	p.Ala125Glu	missense_variant	3/6	ENST00000256178.8
IRAG1-AS1	NR_046374.1	n.308-22064G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYVE1	ENST00000256178.8	c.374C>A	p.Ala125Glu	missense_variant	3/6	1	NM_006691.4	P1
IRAG1-AS1	ENST00000663840.1	n.285+22421G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

May 27, 2022

The c.374C>A (p.A125E) alteration is located in exon 3 (coding exon 3) of the LYVE1 gene. This alteration results from a C to A substitution at nucleotide position 374, causing the alanine (A) at amino acid position 125 to be replaced by a glutamic acid (E). 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	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.080
DANN	Benign	0.54
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.068
Sift	Benign	0.81	T
Sift4G	Benign	0.56	T
Polyphen		0.014	B
Vest4		0.23
MutPred		0.56		Gain of sheet (P = 0.039);
MVP		0.048
MPC		0.096
ClinPred		0.057	T
GERP RS		-4.8
Varity_R		0.089
gMVP		0.49

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: rs949259277; hg19: chr11-10585510;