6-43509619-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001012974.4(LRRC73):​c.167C>A​(p.Thr56Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,452,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T56A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

LRRC73
NM_001012974.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.35

Publications

0 publications found
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]
POLR1C Gene-Disease associations (from GenCC):
  • hypomyelinating leukodystrophy 11
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Treacher Collins syndrome 3
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
  • Treacher-Collins syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08319977).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRRC73NM_001012974.4 linkc.167C>A p.Thr56Lys missense_variant Exon 1 of 6 ENST00000372441.2 NP_001012992.1 Q5JTD7
LRRC73NM_001271882.2 linkc.-98+587C>A intron_variant Intron 1 of 5 NP_001258811.1 Q5JTD7Q3B825

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRRC73ENST00000372441.2 linkc.167C>A p.Thr56Lys missense_variant Exon 1 of 6 1 NM_001012974.4 ENSP00000361518.1 Q5JTD7
POLR1CENST00000428025.6 linkc.-286G>T upstream_gene_variant 4 ENSP00000395401.2 D6RDJ3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1452664
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
722224
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33366
American (AMR)
AF:
0.00
AC:
0
AN:
43754
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25966
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39464
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85284
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50766
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4770
European-Non Finnish (NFE)
AF:
0.0000171
AC:
19
AN:
1109358
Other (OTH)
AF:
0.0000501
AC:
3
AN:
59936
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 01, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.167C>A (p.T56K) alteration is located in exon 1 (coding exon 1) of the LRRC73 gene. This alteration results from a C to A substitution at nucleotide position 167, causing the threonine (T) at amino acid position 56 to be replaced by a lysine (K). 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
0.16
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
22
DANN
Benign
0.93
DEOGEN2
Benign
0.0063
T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.083
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.32
N
PhyloP100
7.3
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
0.28
N
REVEL
Benign
0.12
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.21
MutPred
0.35
Gain of ubiquitination at T56 (P = 0.0238);
MVP
0.082
MPC
0.90
ClinPred
0.73
D
GERP RS
4.1
PromoterAI
-0.026
Neutral
Varity_R
0.10
gMVP
0.24
Mutation Taster
=87/13
polymorphism

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

Other links and lift over

dbSNP: rs1337571565; hg19: chr6-43477357; API