15-99287839-A-T

Variant names:

• chr15-99287839-A-T
• rs777683476
• NM_144598.5:c.273A>T

Variant summary

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

The NM_001321679.2(LRRC28):​c.-190A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,654 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: 0.0000014 (0 hom.)
• Consequence: LRRC28 NM_001321679.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

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 rank	MANE	Protein	UniProt
LRRC28	NM_144598.5	c.273A>T	p.Gln91His	missense_variant	Exon 5 of 10	ENST00000301981.8	NP_653199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC28	ENST00000301981.8	c.273A>T	p.Gln91His	missense_variant	Exon 5 of 10	1	NM_144598.5	ENSP00000304923.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460654 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726646

Gnomad4 AFR exome AF: 0.0000598

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.273A>T (p.Q91H) alteration is located in exon 5 (coding exon 4) of the LRRC28 gene. This alteration results from a A to T substitution at nucleotide position 273, causing the glutamine (Q) at amino acid position 91 to be replaced by a histidine (H). 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	0.61
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.5	L;L;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.042	D;D;D;D
Sift4G	Benign	0.10	T;T;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.77
MutPred		0.47		Loss of ubiquitination at K89 (P = 0.1453);Loss of ubiquitination at K89 (P = 0.1453);.;Loss of ubiquitination at K89 (P = 0.1453);
MVP		0.79
MPC		0.49
ClinPred		0.98	D
GERP RS		-0.49
Varity_R		0.36
gMVP		0.62

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: rs777683476; hg19: chr15-99828044;