chr5-81309022-A-T

Variant names:

• chr5-81309022-A-T
• NM_001131035.2:c.612A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001131035.2(ZCCHC9):​c.612A>T​(p.Lys204Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZCCHC9 NM_001131035.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

Genes affected

ZCCHC9 (HGNC:25424): (zinc finger CCHC-type containing 9) Enables RNA binding activity. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACOT12 (HGNC:24436): (acyl-CoA thioesterase 12) Enables identical protein binding activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid metabolic process. Predicted to act upstream of or within acetyl-CoA metabolic process. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC9	NM_001131035.2	c.612A>T	p.Lys204Asn	missense_variant	Exon 4 of 6	ENST00000407610.8	NP_001124507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZCCHC9	ENST00000407610.8	c.612A>T	p.Lys204Asn	missense_variant	Exon 4 of 6	2	NM_001131035.2	ENSP00000385047.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459874 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.612A>T (p.K204N) alteration is located in exon 4 (coding exon 3) of the ZCCHC9 gene. This alteration results from a A to T substitution at nucleotide position 612, causing the lysine (K) at amino acid position 204 to be replaced by an asparagine (N). 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	0.81
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T;T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	.;.;.;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	2.0	M;M;M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.66
MutPred		0.32		Loss of ubiquitination at K204 (P = 0.0063);Loss of ubiquitination at K204 (P = 0.0063);Loss of ubiquitination at K204 (P = 0.0063);Loss of ubiquitination at K204 (P = 0.0063);
MVP		0.19
MPC		0.57
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-80604841;