NM_144598.5:c.273A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144598.5(LRRC28):​c.273A>T​(p.Gln91His) variant causes a missense 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_144598.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144598.5. 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
	LRRC28	NM_144598.5	MANE Select	c.273A>T	p.Gln91His	missense	Exon 5 of 10	NP_653199.2
	LRRC28	NM_001321679.2		c.-190A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 9	NP_001308608.1	Q8NB41
	LRRC28	NM_001321680.2		c.-190A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 9	NP_001308609.1	Q8NB41

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC28	ENST00000301981.8	TSL:1 MANE Select	c.273A>T	p.Gln91His	missense	Exon 5 of 10	ENSP00000304923.3	Q86X40-1
	LRRC28	ENST00000447360.6	TSL:1	c.273A>T	p.Gln91His	missense	Exon 5 of 9	ENSP00000404520.2	Q86X40-2
	LRRC28	ENST00000331450.9	TSL:1	c.209+11223A>T		intron	N/A	ENSP00000332035.5	Q8WUS2

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

African (AFR) AF: 0.0000598 AC: 2 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111366

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.39
Sift	Benign	0.042	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.47		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
Mutation Taster		=48/52	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: rs777683476; hg19: chr15-99828044;