15-99287834-C-T

Position:

• chr15-99287834-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144598.5(LRRC28):​c.268C>T​(p.Leu90Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,460,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: LRRC28 NM_144598.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

Genes affected

LRRC28 (HGNC:28355): (leucine rich repeat containing 28)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC28	NM_144598.5	c.268C>T	p.Leu90Phe	missense_variant	5/10	ENST00000301981.8	NP_653199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC28	ENST00000301981.8	c.268C>T	p.Leu90Phe	missense_variant	5/10	1	NM_144598.5	ENSP00000304923.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250452 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460322 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 726484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.268C>T (p.L90F) alteration is located in exon 5 (coding exon 4) of the LRRC28 gene. This alteration results from a C to T substitution at nucleotide position 268, causing the leucine (L) at amino acid position 90 to be replaced by a phenylalanine (F). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.;T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.92
MutPred		0.80		Gain of methylation at K89 (P = 0.0313);Gain of methylation at K89 (P = 0.0313);.;Gain of methylation at K89 (P = 0.0313);
MVP		0.93
MPC		0.53
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.73

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: rs866339344; hg19: chr15-99828039;