7-149432534-C-T

Position:

• chr7-149432534-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015694.3(ZNF777):​c.1738G>A​(p.Glu580Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000021 (0 hom.)
• Consequence: ZNF777 NM_015694.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

Genes affected

ZNF777 (HGNC:22213): (zinc finger protein 777) 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 by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18405586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF777	NM_015694.3	c.1738G>A	p.Glu580Lys	missense_variant	6/6	ENST00000247930.5	NP_056509.2
ZNF777	XM_005249980.4	c.1870G>A	p.Glu624Lys	missense_variant	6/6		XP_005250037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF777	ENST00000247930.5	c.1738G>A	p.Glu580Lys	missense_variant	6/6	1	NM_015694.3	ENSP00000247930	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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 11, 2023

The c.1738G>A (p.E580K) alteration is located in exon 6 (coding exon 5) of the ZNF777 gene. This alteration results from a G to A substitution at nucleotide position 1738, causing the glutamic acid (E) at amino acid position 580 to be replaced by a lysine (K). 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	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.30	N
MutationTaster	Benign	0.70	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.13
Sift	Benign	0.072	T
Sift4G	Benign	0.39	T
Polyphen		0.88	P
Vest4		0.16
MutPred		0.66		Gain of methylation at E580 (P = 0.0012);
MVP		0.14
MPC		0.78
ClinPred		0.48	T
GERP RS		4.6
gMVP		0.75

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: chr7-149129625;