11-32602925-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001008391.4(CCDC73):c.3126C>G(p.Ser1042Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,748 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. S1042T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CCDC73
NM_001008391.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.526

Variant links:

Genes affected

CCDC73 (HGNC:23261): (coiled-coil domain containing 73)

CCDC73 links:

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]

EIF3M links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05024129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC73	NM_001008391.4 link	c.3126C>G	p.Ser1042Arg	missense_variant	Exon 18 of 18	ENST00000335185.10	NP_001008392.2	Q6ZRK6-1
EIF3M	NM_006360.6 link	c.*526G>C		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	UniProt
CCDC73	ENST00000335185.10 link	c.3126C>G	p.Ser1042Arg	missense_variant	Exon 18 of 18	2	NM_001008391.4	ENSP00000335325.5	Q6ZRK6-1
EIF3M	ENST00000531120.6 link	c.*526G>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_006360.6	ENSP00000436049.1	Q7L2H7-1
CCDC73	ENST00000528333.1 link	c.231C>G	p.Ser77Arg	missense_variant	Exon 2 of 2	3		ENSP00000434365.1	H0YDV2
EIF3M	ENST00000524896.5 link	c.*526G>C		downstream_gene_variant		2		ENSP00000436787.1	Q7L2H7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249110

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460748

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726686

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33446

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44672

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26118

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39658

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86098

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53408

Gnomad4 NFE exome

AF:

0.0000135

AC:

AN:

1111256

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60330

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3126C>G (p.S1042R) alteration is located in exon 18 (coding exon 17) of the CCDC73 gene. This alteration results from a C to G substitution at nucleotide position 3126, causing the serine (S) at amino acid position 1042 to be replaced by an arginine (R). 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

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.46

M_CAP

Benign

0.0018

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.7

REVEL

Benign

0.059

Sift

Uncertain

0.012

Sift4G

Uncertain

0.016

Polyphen

0.010

Vest4

0.14

MutPred

0.24

Gain of solvent accessibility (P = 0.0584);

MVP

0.11

MPC

0.15

ClinPred

0.042

GERP RS

-1.4

Varity_R

0.085

gMVP

0.16

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over