6-43507587-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001012974.4(LRRC73):c.749T>C(p.Ile250Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRRC73 NM_001012974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

Genes affected

LRRC73 (HGNC:21375): (leucine rich repeat containing 73)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC73	NM_001012974.4	c.749T>C	p.Ile250Thr	missense_variant	5/6	ENST00000372441.2
LRRC73	NM_001271882.2	c.380T>C	p.Ile127Thr	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC73	ENST00000372441.2	c.749T>C	p.Ile250Thr	missense_variant	5/6	1	NM_001012974.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250452 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

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.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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

May 26, 2023

The c.749T>C (p.I250T) alteration is located in exon 5 (coding exon 5) of the LRRC73 gene. This alteration results from a T to C substitution at nucleotide position 749, causing the isoleucine (I) at amino acid position 250 to be replaced by a threonine (T). 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	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.068	T
Polyphen		0.99	D
Vest4		0.89
MutPred		0.71		Gain of disorder (P = 0.0369);
MVP		0.28
MPC		2.0
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.53
gMVP		0.63

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: rs778487300; hg19: chr6-43475325;