5-62579680-C-G

Variant names:

• chr5-62579680-C-G
• rs1436623481
• NM_181506.5:c.242C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181506.5(LRRC70):​c.242C>G​(p.Thr81Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: LRRC70 NM_181506.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.558

Genes affected

LRRC70 (HGNC:35155): (leucine rich repeat containing 70) Involved in positive regulation of response to cytokine stimulus. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

IPO11 (HGNC:20628): (importin 11) Importins, including IPO11, are a members of the karyopherin/importin-beta family of transport receptors (see KPNB1; 602738) that mediate nucleocytoplasmic transport of protein and RNA cargoes (Plafker and Macara, 2000 [PubMed 11032817]).[supplied by OMIM, Sep 2008]

IPO11-LRRC70 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04258448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC70	NM_181506.5	c.242C>G	p.Thr81Arg	missense_variant	Exon 2 of 2	ENST00000334994.6	NP_852607.3
IPO11	NM_016338.5	c.2583-11897C>G		intron_variant	Intron 27 of 29	ENST00000325324.11	NP_057422.3
IPO11	NM_001134779.2	c.2703-11897C>G		intron_variant	Intron 27 of 29		NP_001128251.1
IPO11-LRRC70	NR_073584.1	n.201+745C>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC70	ENST00000334994.6	c.242C>G	p.Thr81Arg	missense_variant	Exon 2 of 2	1	NM_181506.5	ENSP00000399441.1
IPO11	ENST00000325324.11	c.2583-11897C>G		intron_variant	Intron 27 of 29	1	NM_016338.5	ENSP00000316651.6
IPO11	ENST00000424533.5	n.*73+197C>G		intron_variant	Intron 28 of 28	2		ENSP00000395685.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000662 AC: 1 AN: 151086 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000413

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 687960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00

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

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242C>G (p.T81R) alteration is located in exon 2 (coding exon 1) of the LRRC70 gene. This alteration results from a C to G substitution at nucleotide position 242, causing the threonine (T) at amino acid position 81 to be replaced by an arginine (R). 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	0.071
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.2
DANN	Benign	0.91
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.15	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.027
Sift	Benign	0.48	T
Sift4G	Benign	0.44	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.38		Gain of methylation at T81 (P = 0.0228);
MVP		0.085
ClinPred		0.031	T
GERP RS		0.20
Varity_R		0.12
gMVP		0.59

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: rs1436623481; hg19: chr5-61875507;