7-128028716-G-T

Variant names:

• chr7-128028716-G-T
• rs117070316
• NM_022143.5:c.1925C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_022143.5(LRRC4):​c.1925C>A​(p.Thr642Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,613,928 control chromosomes in the GnomAD database, including 741 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T642I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (49 hom., cov: 32)
  • Exomes 𝑓: 0.029 (692 hom.)
• Consequence: LRRC4 NM_022143.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003698051).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3223/152204) while in subpopulation NFE AF = 0.032 (2177/68014). AF 95% confidence interval is 0.0309. There are 49 homozygotes in GnomAd4. There are 1495 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3223 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022143.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC4	NM_022143.5	MANE Select	c.1925C>A	p.Thr642Asn	missense	Exon 2 of 2	NP_071426.1	Q9HBW1
	SND1	NM_014390.4	MANE Select	c.1779+37660G>T		intron	N/A	NP_055205.2	Q7KZF4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC4	ENST00000249363.4	TSL:1 MANE Select	c.1925C>A	p.Thr642Asn	missense	Exon 2 of 2	ENSP00000249363.3	Q9HBW1
	SND1	ENST00000354725.8	TSL:1 MANE Select	c.1779+37660G>T		intron	N/A	ENSP00000346762.3	Q7KZF4
	LRRC4	ENST00000944855.1		c.1925C>A	p.Thr642Asn	missense	Exon 3 of 3	ENSP00000614914.1

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3225 AN: 152086 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00691

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0215 AC: 5401 AN: 251182 AF XY: 0.0216

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0268

GnomAD4 exome AF: 0.0291 AC: 42591 AN: 1461724 Hom.: 692 Cov.: 31 AF XY: 0.0286 AC XY: 20769 AN XY: 727170

African (AFR) AF: 0.00603 AC: 202 AN: 33474

American (AMR) AF: 0.0178 AC: 796 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 879 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00791 AC: 682 AN: 86246

European-Finnish (FIN) AF: 0.0192 AC: 1023 AN: 53414

Middle Eastern (MID) AF: 0.0255 AC: 146 AN: 5734

European-Non Finnish (NFE) AF: 0.0333 AC: 37059 AN: 1111906

Other (OTH) AF: 0.0298 AC: 1802 AN: 60392

GnomAD4 genome AF: 0.0212 AC: 3223 AN: 152204 Hom.: 49 Cov.: 32 AF XY: 0.0201 AC XY: 1495 AN XY: 74408

African (AFR) AF: 0.00689 AC: 286 AN: 41526

American (AMR) AF: 0.0200 AC: 306 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00706 AC: 34 AN: 4816

European-Finnish (FIN) AF: 0.0226 AC: 239 AN: 10590

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2177 AN: 68014

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0289 Hom.: 255

Bravo AF: 0.0213

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0308 AC: 265

ExAC AF: 0.0211 AC: 2560

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0308

EpiControl AF: 0.0383

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.069
Eigen_PC	Benign	0.048
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.057
Sift	Benign	0.038	D
Sift4G	Benign	0.14	T
Polyphen		0.047	B
Vest4		0.15
MPC		0.57
ClinPred		0.0096	T
GERP RS		3.9
Varity_R		0.20
gMVP		0.65
Mutation Taster		=64/36	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117070316; hg19: chr7-127668769; COSMIC: COSV99031256; COSMIC: COSV99031256;