1-70145813-C-A

Position:

• chr1-70145813-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000370952.4(LRRC40):​c.1796G>T​(p.Arg599Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000853 in 1,588,222 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R599Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (4 hom.)
• Consequence: LRRC40 ENST00000370952.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37

Genes affected

LRRC40 (HGNC:26004): (leucine rich repeat containing 40) Predicted to enable protein serine/threonine phosphatase activity. Predicted to be involved in signal transduction. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC7 (HGNC:18531): (leucine rich repeat containing 7) Predicted to be involved in several processes, including establishment or maintenance of epithelial cell apical/basal polarity; positive regulation of neuron projection development; and receptor clustering. Located in several cellular components, including centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053854853).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC40	NM_017768.5	c.1796G>T	p.Arg599Leu	missense_variant	15/15	ENST00000370952.4	NP_060238.3
LRRC40	XM_011541763.2	c.1142G>T	p.Arg381Leu	missense_variant	13/13		XP_011540065.1
LRRC40	XM_047424520.1	c.1142G>T	p.Arg381Leu	missense_variant	13/13		XP_047280476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC40	ENST00000370952.4	c.1796G>T	p.Arg599Leu	missense_variant	15/15	1	NM_017768.5	ENSP00000359990	P1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000621 AC: 155 AN: 249694 Hom.: 1 AF XY: 0.000644 AC XY: 87 AN XY: 135008

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000702

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000875 AC: 1257 AN: 1435964 Hom.: 4 Cov.: 26 AF XY: 0.000873 AC XY: 625 AN XY: 716108

Gnomad4 AFR exome AF: 0.000243

Gnomad4 AMR exome AF: 0.000698

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000943

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74442

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000770 Hom.: 1

Bravo AF: 0.000714

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000659 AC: 80

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 03, 2022

The c.1796G>T (p.R599L) alteration is located in exon 15 (coding exon 15) of the LRRC40 gene. This alteration results from a G to T substitution at nucleotide position 1796, causing the arginine (R) at amino acid position 599 to be replaced by a leucine (L). 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	0.84
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.091	T
Polyphen		1.0	D
Vest4		0.72
MVP		0.80
MPC		0.44
ClinPred		0.15	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.69

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: rs145973226; hg19: chr1-70611496;