20-6041498-G-A

Position:

• chr20-6041498-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152611.5(LRRN4):​c.1747C>T​(p.Pro583Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,406,462 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRN4 NM_152611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRN4	NM_152611.5	c.1747C>T	p.Pro583Ser	missense_variant	5/5	ENST00000378858.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRN4	ENST00000378858.5	c.1747C>T	p.Pro583Ser	missense_variant	5/5	1	NM_152611.5	P1
LRRN4	ENST00000698795.1	c.*904C>T		3_prime_UTR_variant	5/5
LRRN4	ENST00000698796.1	n.2038C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1406462 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 693264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

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

Mar 11, 2022

The c.1747C>T (p.P583S) alteration is located in exon 5 (coding exon 4) of the LRRN4 gene. This alteration results from a C to T substitution at nucleotide position 1747, causing the proline (P) at amino acid position 583 to be replaced by a serine (S). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.83		Loss of catalytic residue at P582 (P = 0.0117);
MVP		0.79
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-6022144;