7-128028955-G-A

Position:

• chr7-128028955-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022143.5(LRRC4):​c.1686C>T​(p.Ala562=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,608,504 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (46 hom.)
• Consequence: LRRC4 NM_022143.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.99

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 7-128028955-G-A is Benign according to our data. Variant chr7-128028955-G-A is described in ClinVar as [Benign]. Clinvar id is 781113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.99 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC4	NM_022143.5	c.1686C>T	p.Ala562=	synonymous_variant	2/2	ENST00000249363.4	NP_071426.1
SND1	NM_014390.4	c.1779+37899G>A		intron_variant		ENST00000354725.8	NP_055205.2
LRRC4	XM_011516461.4	c.1686C>T	p.Ala562=	synonymous_variant	3/3		XP_011514763.1
LRRC4	XM_047420695.1	c.1686C>T	p.Ala562=	synonymous_variant	3/3		XP_047276651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC4	ENST00000249363.4	c.1686C>T	p.Ala562=	synonymous_variant	2/2	1	NM_022143.5	ENSP00000249363	P1
SND1	ENST00000354725.8	c.1779+37899G>A		intron_variant		1	NM_014390.4	ENSP00000346762	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2221 AN: 152184 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00399 AC: 946 AN: 236950 Hom.: 14 AF XY: 0.00285 AC XY: 365 AN XY: 128134

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.00245

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000465

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00180 AC: 2619 AN: 1456202 Hom.: 46 Cov.: 31 AF XY: 0.00153 AC XY: 1105 AN XY: 723758

Gnomad4 AFR exome AF: 0.0531

Gnomad4 AMR exome AF: 0.00404

Gnomad4 ASJ exome AF: 0.00223

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.0146 AC: 2222 AN: 152302 Hom.: 62 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74466

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00633 Hom.: 15

Bravo AF: 0.0170

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.2
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs74330692; hg19: chr7-127669008;