1-227655125-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367909.1(ZNF678):c.875C>G(p.Pro292Arg) 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 1,461,156 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF678 NM_001367909.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

ZNF678 (HGNC:28652): (zinc finger protein 678) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32522562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF678	NM_001367909.1	c.875C>G	p.Pro292Arg	missense_variant	4/4	ENST00000343776.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF678	ENST00000343776.10	c.875C>G	p.Pro292Arg	missense_variant	4/4	1	NM_001367909.1	P1
ZNF678	ENST00000397097.4	c.875C>G	p.Pro292Arg	missense_variant	2/2	1		P1
ZNF678	ENST00000608949.5	c.226+649C>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461156 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

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

Jan 10, 2022

The c.1040C>G (p.P347R) alteration is located in exon 4 (coding exon 4) of the ZNF678 gene. This alteration results from a C to G substitution at nucleotide position 1040, causing the proline (P) at amino acid position 347 to be replaced by an arginine (R). 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	0.64
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.087
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.0032	N
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-7.4	D;.
REVEL	Benign	0.16
Sift	Uncertain	0.014	D;.
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.21
MutPred		0.43		Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);
MVP		0.16
MPC		0.073
ClinPred		0.96	D
GERP RS		1.6
Varity_R		0.14
gMVP		0.0087

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: rs1659197156; hg19: chr1-227842826;