15-99287273-A-G

Position:

• chr15-99287273-A-G

Variant summary

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

The ENST00000301981.8(LRRC28):​c.226A>G​(p.Asn76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,419,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: LRRC28 ENST00000301981.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53

Genes affected

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

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/exons	MANE	Protein	UniProt
LRRC28	NM_144598.5	c.226A>G	p.Asn76Asp	missense_variant	4/10	ENST00000301981.8	NP_653199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC28	ENST00000301981.8	c.226A>G	p.Asn76Asp	missense_variant	4/10	1	NM_144598.5	ENSP00000304923	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1419038 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 703986

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: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 10, 2024

The c.226A>G (p.N76D) alteration is located in exon 4 (coding exon 3) of the LRRC28 gene. This alteration results from a A to G substitution at nucleotide position 226, causing the asparagine (N) at amino acid position 76 to be replaced by an aspartic acid (D). 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	0.44
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T;.;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.76	N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.36	T;D;T;D
Sift4G	Uncertain	0.060	T;T;T;T
Polyphen		0.98	D;D;.;.
Vest4		0.78
MutPred		0.46		Gain of catalytic residue at N76 (P = 0.078);Gain of catalytic residue at N76 (P = 0.078);.;Gain of catalytic residue at N76 (P = 0.078);
MVP		0.68
MPC		0.12
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.35
gMVP		0.46

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: chr15-99827478;