7-102934523-C-T

Variant names:

• chr7-102934523-C-T
• rs149650054
• NM_001031692.3:c.610C>T

Variant summary

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

The NM_001031692.3(LRRC17):​c.610C>T​(p.Arg204Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000354 in 1,607,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: LRRC17 NM_001031692.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

Genes affected

LRRC17 (HGNC:16895): (leucine rich repeat containing 17) Predicted to be involved in bone marrow development and negative regulation of osteoclast differentiation. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

FBXL13 (HGNC:21658): (F-box and leucine rich repeat protein 13) Members of the F-box protein family, such as FBXL13, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

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=0.1462462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC17	NM_001031692.3	c.610C>T	p.Arg204Trp	missense_variant	Exon 2 of 4	ENST00000339431.9	NP_001026862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC17	ENST00000339431.9	c.610C>T	p.Arg204Trp	missense_variant	Exon 2 of 4	1	NM_001031692.3	ENSP00000344242.4
FBXL13	ENST00000440067.4	c.995-2590G>A		intron_variant	Intron 9 of 20	3		ENSP00000390126.2

Frequencies

GnomAD3 genomes AF: 0.0000411 AC: 6 AN: 146104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000294

Gnomad EAS AF: 0.000587

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000301

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 249480 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461714 Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000410 AC: 6 AN: 146226 Hom.: 0 Cov.: 32 AF XY: 0.0000422 AC XY: 3 AN XY: 71022

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000294

Gnomad4 EAS AF: 0.000588

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000301

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.610C>T (p.R204W) alteration is located in exon 2 (coding exon 1) of the LRRC17 gene. This alteration results from a C to T substitution at nucleotide position 610, causing the arginine (R) at amino acid position 204 to be replaced by a tryptophan (W). 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	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.98	D;D
Vest4		0.34
MutPred		0.36		Gain of ubiquitination at K201 (P = 0.0354);Gain of ubiquitination at K201 (P = 0.0354);
MVP		0.79
MPC		0.47
ClinPred		0.17	T
GERP RS		3.1
Varity_R		0.095
gMVP		0.50

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: rs149650054; hg19: chr7-102574970;