6-43509716-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001012974.4(LRRC73):​c.70G>A​(p.Gly24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,439,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

LRRC73
NM_001012974.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52
Variant links:
Genes affected
LRRC73 (HGNC:21375): (leucine rich repeat containing 73)
POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08316186).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRC73NM_001012974.4 linkc.70G>A p.Gly24Ser missense_variant 1/6 ENST00000372441.2 NP_001012992.1 Q5JTD7
LRRC73NM_001271882.2 linkc.-98+490G>A intron_variant NP_001258811.1 Q5JTD7Q3B825

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRC73ENST00000372441.2 linkc.70G>A p.Gly24Ser missense_variant 1/61 NM_001012974.4 ENSP00000361518.1 Q5JTD7
POLR1CENST00000428025 linkc.-189C>T 5_prime_UTR_premature_start_codon_gain_variant 1/64 ENSP00000395401.2 D6RDJ3
POLR1CENST00000428025 linkc.-189C>T 5_prime_UTR_variant 1/64 ENSP00000395401.2 D6RDJ3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000479
AC:
1
AN:
208820
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
116676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000107
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000208
AC:
3
AN:
1439076
Hom.:
0
Cov.:
31
AF XY:
0.00000280
AC XY:
2
AN XY:
715534
show subpopulations
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:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 27, 2024The c.70G>A (p.G24S) alteration is located in exon 1 (coding exon 1) of the LRRC73 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glycine (G) at amino acid position 24 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
0.14
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0064
T
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.22
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.083
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.095
N
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
0.76
N
REVEL
Benign
0.052
Sift
Benign
0.85
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.12
MutPred
0.40
Gain of phosphorylation at G24 (P = 0.0412);
MVP
0.043
MPC
0.74
ClinPred
0.46
T
GERP RS
4.1
Varity_R
0.078
gMVP
0.28

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1017504534; hg19: chr6-43477454; API