3-26710336-G-A

Variant names:

• chr3-26710336-G-A
• rs956953900
• NM_052953.4:c.664G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_052953.4(LRRC3B):​c.664G>A​(p.Val222Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V222L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LRRC3B NM_052953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.14
• Publications: 0 publications found

Genes affected

LRRC3B (HGNC:28105): (leucine rich repeat containing 3B) The protein encoded by this gene is a tumor suppressor, with lowered expression levels found in gastric, renal, colorectal, lung, and breast cancer tissues. The promoter of this gene is frequently hypermethylated in these cancer tissues, although the hypermethylation does not appear to be the cause of the reduced expression of this gene. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3187363).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052953.4. 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
	LRRC3B	NM_052953.4	MANE Select	c.664G>A	p.Val222Ile	missense	Exon 2 of 2	NP_443185.1	Q96PB8
	LRRC3B	NM_001317808.2		c.664G>A	p.Val222Ile	missense	Exon 2 of 2	NP_001304737.1	Q96PB8
	LRRC3B	NM_001317809.2		c.664G>A	p.Val222Ile	missense	Exon 2 of 2	NP_001304738.1	Q96PB8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC3B	ENST00000396641.7	TSL:1 MANE Select	c.664G>A	p.Val222Ile	missense	Exon 2 of 2	ENSP00000379880.2	Q96PB8
	LRRC3B	ENST00000417744.5	TSL:1	c.664G>A	p.Val222Ile	missense	Exon 3 of 3	ENSP00000406370.1	Q96PB8
	LRRC3B	ENST00000456208.2	TSL:1	c.664G>A	p.Val222Ile	missense	Exon 3 of 3	ENSP00000394940.2	Q96PB8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461738 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.14
Sift	Benign	0.31	T
Sift4G	Benign	0.31	T
Polyphen		0.46	P
Vest4		0.22
MutPred		0.35		Gain of catalytic residue at V222 (P = 0.0568)
MVP		0.87
MPC		1.4
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.12
gMVP		0.63
Mutation Taster		=33/67	disease causing

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: rs956953900; hg19: chr3-26751827;