6-43509775-C-G

Variant summary

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

The NM_001012974.4(LRRC73):​c.11G>C​(p.Ser4Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

LRRC73
NM_001012974.4 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.43
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]

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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=0.12373197).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRC73NM_001012974.4 linkc.11G>C p.Ser4Thr missense_variant 1/6 ENST00000372441.2 NP_001012992.1 Q5JTD7
LRRC73NM_001271882.2 linkc.-98+431G>C intron_variant NP_001258811.1 Q5JTD7Q3B825

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRC73ENST00000372441.2 linkc.11G>C p.Ser4Thr missense_variant 1/61 NM_001012974.4 ENSP00000361518.1 Q5JTD7
POLR1CENST00000428025 linkc.-130C>G 5_prime_UTR_variant 1/64 ENSP00000395401.2 D6RDJ3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 28, 2024The c.11G>C (p.S4T) alteration is located in exon 1 (coding exon 1) of the LRRC73 gene. This alteration results from a G to C substitution at nucleotide position 11, causing the serine (S) at amino acid position 4 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
Benign
0.19
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.58
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0038
T
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.79
T
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.56
N
REVEL
Benign
0.11
Sift
Uncertain
0.021
D
Sift4G
Benign
0.077
T
Polyphen
0.0020
B
Vest4
0.12
MutPred
0.31
Gain of sheet (P = 0.0149);
MVP
0.043
MPC
0.73
ClinPred
0.70
D
GERP RS
3.8
Varity_R
0.25
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-43477513; API