4-17884726-T-C

Position:

• chr4-17884726-T-C

Variant summary

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

The NM_001166139.2(LCORL):​c.803A>G​(p.Tyr268Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000449 in 1,335,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: LCORL NM_001166139.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCORL	NM_001394446.1	c.776+1342A>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+1342A>G		intron_variant		5	NM_001394446.1	ENSP00000490600.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000449 AC: 6 AN: 1335434 Hom.: 0 Cov.: 32 AF XY: 0.00000458 AC XY: 3 AN XY: 654440

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: 0.0000298

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000285

Gnomad4 OTH exome AF: 0.0000181

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

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 20, 2024

The c.803A>G (p.Y268C) 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 803, causing the tyrosine (Y) at amino acid position 268 to be replaced by a cysteine (C). 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	0.20
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.056	T;T
Sift4G	Benign	0.11	T;T
Vest4		0.66
MVP		0.46
MPC		1.4
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.26
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: rs1261089709; hg19: chr4-17886349;