19-53237046-G-T

Variant summary

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

The NM_182609.4(ZNF677):c.1681C>A(p.His561Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZNF677 NM_182609.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

ZNF677 (HGNC:28730): (zinc finger protein 677) 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF677	NM_182609.4	c.1681C>A	p.His561Asn	missense_variant	5/5	ENST00000598513.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF677	ENST00000598513.6	c.1681C>A	p.His561Asn	missense_variant	5/5	1	NM_182609.4	P1
ZNF677	ENST00000333952.8	c.1681C>A	p.His561Asn	missense_variant	3/3	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448060 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720116

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 06, 2023

The c.1681C>A (p.H561N) alteration is located in exon 5 (coding exon 3) of the ZNF677 gene. This alteration results from a C to A substitution at nucleotide position 1681, causing the histidine (H) at amino acid position 561 to be replaced by an asparagine (N). 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	0.059
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	15
Dann	Benign	0.72
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.011	N
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.43	T
Sift4G	Uncertain	0.026	D;D
Polyphen		0.98	D;D
Vest4		0.39
MutPred		0.64		Gain of ubiquitination at K563 (P = 0.1132);Gain of ubiquitination at K563 (P = 0.1132);
MVP		0.96
MPC		0.052
ClinPred		0.75	D
GERP RS		1.4
Varity_R		0.22
gMVP		0.065

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: chr19-53740299;