16-87411636-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015144.3(ZCCHC14):c.3085G>A(p.Val1029Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZCCHC14 NM_015144.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

ZCCHC14 (HGNC:24134): (zinc finger CCHC-type containing 14) Predicted to enable nucleic acid binding activity; phosphatidylinositol binding activity; and zinc ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0675863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC14	NM_015144.3	c.3085G>A	p.Val1029Met	missense_variant	12/13	ENST00000671377.2
ZCCHC14	XM_005255858.4	c.3085G>A	p.Val1029Met	missense_variant	12/12
ZCCHC14	XM_017023082.3	c.2566G>A	p.Val856Met	missense_variant	12/12
ZCCHC14	XR_243401.4	n.3871G>A		non_coding_transcript_exon_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC14	ENST00000671377.2	c.3085G>A	p.Val1029Met	missense_variant	12/13		NM_015144.3	P1
ZCCHC14	ENST00000268616.9	c.2674G>A	p.Val892Met	missense_variant	12/13	1
ZCCHC14	ENST00000568020.6	c.2707G>A	p.Val903Met	missense_variant, NMD_transcript_variant	12/14	1
ZCCHC14	ENST00000561928.1	c.2326G>A	p.Val776Met	missense_variant	10/10	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461614 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.2674G>A (p.V892M) alteration is located in exon 12 (coding exon 12) of the ZCCHC14 gene. This alteration results from a G to A substitution at nucleotide position 2674, causing the valine (V) at amino acid position 892 to be replaced by a methionine (M). 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	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Uncertain	0.97
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.55	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.049
Sift	Benign	0.35	T
Sift4G	Benign	0.18	T
Polyphen		0.016	B
Vest4		0.16
MutPred		0.25		Loss of catalytic residue at V892 (P = 0.1131);
MVP		0.043
MPC		0.25
ClinPred		0.37	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.055
gMVP		0.18

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

Other links and lift over

dbSNP: rs200637893; hg19: chr16-87445242;