NM_001008391.4:c.3125G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001008391.4(CCDC73):​c.3125G>C​(p.Ser1042Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. S1042R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CCDC73
NM_001008391.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.845
Variant links:
Genes affected
CCDC73 (HGNC:23261): (coiled-coil domain containing 73)
EIF3M (HGNC:24460): (eukaryotic translation initiation factor 3 subunit M) This gene encodes a protein that is part of the eurkaryotic translation initiation factor 3 complete (eIF-3) required for protein synthesis. Elevated levels of the encoded protein are present in cancer cell lines. Inactivation of the encoded protein has been shown to interfere with translation of herpes virus mRNAs by preventing the association of mRNAs with the ribosomes. A pseudogene of this gene is located on the X chromosome. [provided by RefSeq, Dec 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05369839).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC73NM_001008391.4 linkc.3125G>C p.Ser1042Thr missense_variant Exon 18 of 18 ENST00000335185.10 NP_001008392.2 Q6ZRK6-1
EIF3MNM_006360.6 linkc.*527C>G 3_prime_UTR_variant Exon 11 of 11 ENST00000531120.6 NP_006351.2 Q7L2H7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC73ENST00000335185.10 linkc.3125G>C p.Ser1042Thr missense_variant Exon 18 of 18 2 NM_001008391.4 ENSP00000335325.5 Q6ZRK6-1
EIF3MENST00000531120.6 linkc.*527C>G 3_prime_UTR_variant Exon 11 of 11 1 NM_006360.6 ENSP00000436049.1 Q7L2H7-1
CCDC73ENST00000528333.1 linkc.230G>C p.Ser77Thr missense_variant Exon 2 of 2 3 ENSP00000434365.1 H0YDV2
EIF3MENST00000524896.5 linkc.*527C>G downstream_gene_variant 2 ENSP00000436787.1 Q7L2H7-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
32
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:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249156
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135174
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
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:
1460990
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726808
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3125G>C (p.S1042T) alteration is located in exon 18 (coding exon 17) of the CCDC73 gene. This alteration results from a G to C substitution at nucleotide position 3125, causing the serine (S) at amino acid position 1042 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
0.099
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
8.5
DANN
Benign
0.95
DEOGEN2
Benign
0.0098
T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.035
N
LIST_S2
Benign
0.47
T
M_CAP
Benign
0.0042
T
MetaRNN
Benign
0.054
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.61
N
REVEL
Benign
0.021
Sift
Uncertain
0.024
D
Sift4G
Benign
0.46
T
Polyphen
0.23
B
Vest4
0.059
MutPred
0.16
Gain of helix (P = 0.0854);
MVP
0.21
MPC
0.32
ClinPred
0.087
T
GERP RS
-1.3
Varity_R
0.064
gMVP
0.076

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: rs1331078904; hg19: chr11-32624472; API