chr6-43508817-C-T

Position:

• chr6-43508817-C-T

Variant summary

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

The NM_001012974.4(LRRC73):​c.376G>A​(p.Gly126Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRC73 NM_001012974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.01

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, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC73	NM_001012974.4	c.376G>A	p.Gly126Ser	missense_variant	2/6	ENST00000372441.2	NP_001012992.1
LRRC73	NM_001271882.2	c.7G>A	p.Gly3Ser	missense_variant	2/6		NP_001258811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC73	ENST00000372441.2	c.376G>A	p.Gly126Ser	missense_variant	2/6	1	NM_001012974.4	ENSP00000361518.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250636 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460804 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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

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

Jul 09, 2024

The c.376G>A (p.G126S) alteration is located in exon 2 (coding exon 2) of the LRRC73 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the glycine (G) at amino acid position 126 to be replaced by a serine (S). 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	Benign	0.27
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.29
Sift	Benign	0.16	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.52		Loss of catalytic residue at G126 (P = 0.0198);
MVP		0.38
MPC		1.8
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.34
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: rs1204258878; hg19: chr6-43476555;