NM_001008391.4:c.3056C>T

Variant names:

• chr11-32602995-G-A
• rs776502529
• NM_001008391.4:c.3056C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008391.4(CCDC73):​c.3056C>T​(p.Thr1019Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,603,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CCDC73 NM_001008391.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.132
• Publications: 0 publications found

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]

ACMG classification

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=0.08608478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC73	NM_001008391.4	c.3056C>T	p.Thr1019Ile	missense_variant	Exon 18 of 18	ENST00000335185.10	NP_001008392.2
EIF3M	NM_006360.6	c.*596G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000531120.6	NP_006351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC73	ENST00000335185.10	c.3056C>T	p.Thr1019Ile	missense_variant	Exon 18 of 18	2	NM_001008391.4	ENSP00000335325.5
EIF3M	ENST00000531120.6	c.*596G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_006360.6	ENSP00000436049.1
CCDC73	ENST00000528333.1	c.161C>T	p.Thr54Ile	missense_variant	Exon 2 of 2	3		ENSP00000434365.1
EIF3M	ENST00000524896.5	c.*596G>A		downstream_gene_variant		2		ENSP00000436787.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000837 AC: 2 AN: 238880 AF XY: 0.00

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: 0.00000906

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1451540 Hom.: 0 Cov.: 31 AF XY: 0.00000832 AC XY: 6 AN XY: 721572

African (AFR) AF: 0.00 AC: 0 AN: 32700

American (AMR) AF: 0.00 AC: 0 AN: 41960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 83078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1109460

Other (OTH) AF: 0.00 AC: 0 AN: 59976

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3056C>T (p.T1019I) alteration is located in exon 18 (coding exon 17) of the CCDC73 gene. This alteration results from a C to T substitution at nucleotide position 3056, causing the threonine (T) at amino acid position 1019 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.13
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.017
Sift	Benign	0.039	D
Sift4G	Uncertain	0.030	D
Polyphen		0.69	P
Vest4		0.11
MutPred		0.24		Gain of sheet (P = 0.0344);
MVP		0.11
MPC		0.25
ClinPred		0.13	T
GERP RS		1.8
Varity_R		0.047
gMVP		0.11
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs776502529; hg19: chr11-32624541;