20-6041204-C-T

Position:

• chr20-6041204-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_152611.5(LRRN4):​c.2041G>A​(p.Ala681Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,435,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: LRRN4 NM_152611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0510

Genes affected

LRRN4 (HGNC:16208): (leucine rich repeat neuronal 4) Predicted to be involved in long-term memory. Predicted to act upstream of or within visual learning. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09464508).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRN4	NM_152611.5	c.2041G>A	p.Ala681Thr	missense_variant	5/5	ENST00000378858.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRN4	ENST00000378858.5	c.2041G>A	p.Ala681Thr	missense_variant	5/5	1	NM_152611.5	P1
LRRN4	ENST00000698795.1	c.*1198G>A		3_prime_UTR_variant	5/5
LRRN4	ENST00000698796.1	n.2332G>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1435742 Hom.: 0 Cov.: 33 AF XY: 0.00000422 AC XY: 3 AN XY: 711186

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0000236

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: 0.00000182

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.00000756

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 21, 2022

The c.2041G>A (p.A681T) alteration is located in exon 5 (coding exon 4) of the LRRN4 gene. This alteration results from a G to A substitution at nucleotide position 2041, causing the alanine (A) at amino acid position 681 to be replaced by a threonine (T). 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	0.077
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.11
Sift	Benign	0.27	T
Sift4G	Benign	0.40	T
Polyphen		0.66	P
Vest4		0.19
MutPred		0.28		Gain of glycosylation at A681 (P = 0.0651);
MVP		0.24
MPC		0.42
ClinPred		0.30	T
GERP RS		-1.9
Varity_R		0.070
gMVP		0.14

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: rs1341316425; hg19: chr20-6021850; COSMIC: COSV66646184; COSMIC: COSV66646184;