NM_001008391.4:c.3003T>G

Variant names:

• chr11-32611159-A-C
• rs369078499
• NM_001008391.4:c.3003T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001008391.4(CCDC73):​c.3003T>G​(p.Phe1001Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CCDC73 NM_001008391.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.28
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4225085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC73	NM_001008391.4	c.3003T>G	p.Phe1001Leu	missense_variant	Exon 17 of 18	ENST00000335185.10	NP_001008392.2
CCDC73	XM_047427029.1	c.3003T>G	p.Phe1001Leu	missense_variant	Exon 22 of 23		XP_047282985.1
CCDC73	XM_047427030.1	c.3003T>G	p.Phe1001Leu	missense_variant	Exon 17 of 18		XP_047282986.1
CCDC73	XM_047427031.1	c.2745T>G	p.Phe915Leu	missense_variant	Exon 16 of 17		XP_047282987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC73	ENST00000335185.10	c.3003T>G	p.Phe1001Leu	missense_variant	Exon 17 of 18	2	NM_001008391.4	ENSP00000335325.5
CCDC73	ENST00000528333.1	c.136-8139T>G		intron_variant	Intron 1 of 1	3		ENSP00000434365.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249322 AF XY: 0.00000739

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: 0.00000411 AC: 6 AN: 1461570 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727098

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3003T>G (p.F1001L) alteration is located in exon 17 (coding exon 16) of the CCDC73 gene. This alteration results from a T to G substitution at nucleotide position 3003, causing the phenylalanine (F) at amino acid position 1001 to be replaced by a leucine (L). 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	Pathogenic	0.75
BayesDel_addAF	Benign	0.0073	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.082	T
Sift4G	Benign	0.062	T
Polyphen		0.98	D
Vest4		0.56
MutPred		0.15		Loss of sheet (P = 0.0315);
MVP		0.055
MPC		0.14
ClinPred		0.60	D
GERP RS		5.6
Varity_R		0.16
gMVP		0.23
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369078499; hg19: chr11-32632705;