4-17884432-T-C

Position:

• chr4-17884432-T-C

Variant summary

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

The NM_001166139.2(LCORL):​c.1097A>G​(p.Asn366Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 7.2e-7 (0 hom.)
• Consequence: LCORL NM_001166139.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

Genes affected

LCORL (HGNC:30776): (ligand dependent nuclear receptor corepressor like) This gene encodes a transcription factor that appears to function in spermatogenesis. Polymorphisms in this gene are associated with measures of skeletal frame size and adult height. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

LCORL (HGNC:):

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=0.089096695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCORL	NM_001394446.1	c.776+1636A>G		intron_variant		ENST00000635767.2	NP_001381375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCORL	ENST00000635767.2	c.776+1636A>G		intron_variant		5	NM_001394446.1	ENSP00000490600.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398106 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 689624

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 30, 2024

The c.1097A>G (p.N366S) alteration is located in exon 7 (coding exon 7) of the LCORL gene. This alteration results from a A to G substitution at nucleotide position 1097, causing the asparagine (N) at amino acid position 366 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	Benign	0.060
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.0024	.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0083
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.20
Sift	Benign	0.40	T;T
Sift4G	Benign	0.76	T;T
Vest4		0.033
MutPred		0.18		.;Gain of disorder (P = 0.0405);
MVP		0.28
MPC		0.35
ClinPred		0.23	T
GERP RS		4.0
Varity_R		0.040
gMVP		0.057

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: rs1728018267; hg19: chr4-17886055;