7-139405737-A-G

Position:

• chr7-139405737-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016019.5(LUC7L2):​c.460A>G​(p.Lys154Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LUC7L2 NM_016019.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

Genes affected

LUC7L2 (HGNC:21608): (LUC7 like 2, pre-mRNA splicing factor) This gene encodes a protein that contains a C2H2-type zinc finger, coiled-coil region and arginine, serine-rich (RS) domain. A similar protein in mouse interacts with sodium channel modifier 1, and the encoded protein may be involved in the recognition of non-consensus splice donor sites in association with the U1 snRNP spliceosomal subunit. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

FMC1-LUC7L2 (HGNC:44671): (FMC1-LUC7L2 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring C7orf55 (chromosome 7 open reading frame 55) and LUC7L2 (LUC7-like 2) genes on chromosome 7. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27949005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LUC7L2	NM_016019.5	c.460A>G	p.Lys154Glu	missense_variant	5/10	ENST00000354926.9	NP_057103.2
FMC1-LUC7L2	NM_001244584.3	c.658A>G	p.Lys220Glu	missense_variant	6/11		NP_001231513.1
LUC7L2	NM_001270643.2	c.457A>G	p.Lys153Glu	missense_variant	6/11		NP_001257572.1
LUC7L2	NM_001244585.2	c.451A>G	p.Lys151Glu	missense_variant	6/11		NP_001231514.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LUC7L2	ENST00000354926.9	c.460A>G	p.Lys154Glu	missense_variant	5/10	1	NM_016019.5	ENSP00000347005.4
FMC1-LUC7L2	ENST00000541515.3	c.658A>G	p.Lys220Glu	missense_variant	6/11	2		ENSP00000440222.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461160 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726844

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Jun 28, 2024

The c.460A>G (p.K154E) alteration is located in exon 5 (coding exon 5) of the LUC7L2 gene. This alteration results from a A to G substitution at nucleotide position 460, causing the lysine (K) at amino acid position 154 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	0.19
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;.;T;.;.
Eigen	Benign	0.069
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;L;.;.
PROVEAN	Benign	-1.8	N;.;N;.;N
REVEL	Benign	0.16
Sift	Benign	0.23	T;.;T;.;T
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.14, 0.17	.;B;B;.;.
Vest4		0.46
MutPred		0.48		.;.;Loss of ubiquitination at K154 (P = 0.0037);.;.;
MVP		0.21
MPC		2.0, 2.1
ClinPred		0.72	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.87

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: chr7-139090483;