5-81308961-C-T

Variant names:

• chr5-81308961-C-T
• rs369137521
• NM_001131035.2:c.551C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001131035.2(ZCCHC9):​c.551C>T​(p.Ala184Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZCCHC9 NM_001131035.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131035.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC9	NM_001131035.2	MANE Select	c.551C>T	p.Ala184Val	missense	Exon 4 of 6	NP_001124507.1	Q8N567
	ZCCHC9	NM_001131036.2		c.551C>T	p.Ala184Val	missense	Exon 4 of 6	NP_001124508.1	Q8N567
	ZCCHC9	NM_032280.3		c.551C>T	p.Ala184Val	missense	Exon 4 of 6	NP_115656.1	Q8N567

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC9	ENST00000407610.8	TSL:2 MANE Select	c.551C>T	p.Ala184Val	missense	Exon 4 of 6	ENSP00000385047.3	Q8N567
	ZCCHC9	ENST00000380199.9	TSL:1	c.551C>T	p.Ala184Val	missense	Exon 4 of 6	ENSP00000369546.5	Q8N567
	ZCCHC9	ENST00000438268.2	TSL:1	c.551C>T	p.Ala184Val	missense	Exon 4 of 6	ENSP00000412637.2	Q8N567

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152092 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250738 AF XY: 0.00000738

Gnomad AFR exome AF: 0.000123

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460696 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726590

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111600

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74428

African (AFR) AF: 0.0000722 AC: 3 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.54		Loss of catalytic residue at A184 (P = 0.0589)
MVP		0.63
MPC		0.34
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.55
gMVP		0.72
Mutation Taster		=22/78	disease causing

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: rs369137521; hg19: chr5-80604780;