1-227655014-A-G

Variant summary

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

The NM_001367909.1(ZNF678):c.764A>G(p.His255Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ZNF678 NM_001367909.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF678	NM_001367909.1	c.764A>G	p.His255Arg	missense_variant	4/4	ENST00000343776.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF678	ENST00000343776.10	c.764A>G	p.His255Arg	missense_variant	4/4	1	NM_001367909.1	P1
ZNF678	ENST00000397097.4	c.764A>G	p.His255Arg	missense_variant	2/2	1		P1
ZNF678	ENST00000608949.5	c.226+538A>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460510 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726554

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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 26, 2022

The c.929A>G (p.H310R) alteration is located in exon 4 (coding exon 4) of the ZNF678 gene. This alteration results from a A to G substitution at nucleotide position 929, causing the histidine (H) at amino acid position 310 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	0.83
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.0010	N
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.5	D;.
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.31
MutPred		0.57		Gain of MoRF binding (P = 0.018);Gain of MoRF binding (P = 0.018);
MVP		0.63
MPC		0.089
ClinPred		0.86	D
GERP RS		0.53
Varity_R		0.27
gMVP		0.12

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: rs752419331; hg19: chr1-227842715;