7-128028951-G-A

Variant names:

• chr7-128028951-G-A
• NM_022143.5:c.1690C>T

Variant summary

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

The NM_022143.5(LRRC4):​c.1690C>T​(p.Arg564Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,676 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: 0.0000014 (0 hom.)
• Consequence: LRRC4 NM_022143.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

Genes affected

LRRC4 (HGNC:15586): (leucine rich repeat containing 4) Predicted to be involved in modulation of chemical synaptic transmission and synapse organization. Predicted to act upstream of or within synapse organization. Predicted to be located in neuron spine and postsynaptic membrane. Predicted to be active in Schaffer collateral - CA1 synapse; glutamatergic synapse; and plasma membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

SND1 (HGNC:30646): (staphylococcal nuclease and tudor domain containing 1) This gene encodes a transcriptional co-activator that interacts with the acidic domain of Epstein-Barr virus nuclear antigen 2 (EBNA 2), a transcriptional activator that is required for B-lymphocyte transformation. Other transcription factors that interact with this protein are signal transducers and activators of transcription, STATs. This protein is also thought to be essential for normal cell growth. A similar protein in mammals and other organisms is a component of the RNA-induced silencing complex (RISC). [provided by RefSeq, Jul 2016]

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 rank	MANE	Protein	UniProt
LRRC4	NM_022143.5	c.1690C>T	p.Arg564Trp	missense_variant	Exon 2 of 2	ENST00000249363.4	NP_071426.1
SND1	NM_014390.4	c.1779+37895G>A		intron_variant	Intron 16 of 23	ENST00000354725.8	NP_055205.2
LRRC4	XM_011516461.4	c.1690C>T	p.Arg564Trp	missense_variant	Exon 3 of 3		XP_011514763.1
LRRC4	XM_047420695.1	c.1690C>T	p.Arg564Trp	missense_variant	Exon 3 of 3		XP_047276651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC4	ENST00000249363.4	c.1690C>T	p.Arg564Trp	missense_variant	Exon 2 of 2	1	NM_022143.5	ENSP00000249363.3
SND1	ENST00000354725.8	c.1779+37895G>A		intron_variant	Intron 16 of 23	1	NM_014390.4	ENSP00000346762.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455676 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

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

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1690C>T (p.R564W) alteration is located in exon 2 (coding exon 1) of the LRRC4 gene. This alteration results from a C to T substitution at nucleotide position 1690, causing the arginine (R) at amino acid position 564 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.096
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.59		Loss of sheet (P = 0.0043);
MVP		0.34
MPC		1.4
ClinPred		0.99	D
GERP RS		0.085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.60

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: chr7-127669004;