chr7-99573325-A-G

Position:

• chr7-99573325-A-G

Variant summary

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

The NM_138494.3(ZNF655):​c.1217A>G​(p.Lys406Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000034 (0 hom.)
• Consequence: ZNF655 NM_138494.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

ZNF655 (HGNC:30899): (zinc finger protein 655) This gene encodes a zinc finger protein. The zinc finger proteins are involved in DNA binding and protein-protein interactions. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.14898229).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF655	NM_138494.3	c.1217A>G	p.Lys406Arg	missense_variant	3/3	ENST00000252713.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF655	ENST00000252713.9	c.1217A>G	p.Lys406Arg	missense_variant	3/3	1	NM_138494.3	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Dec 31, 2023

The c.1322A>G (p.K441R) alteration is located in exon 4 (coding exon 3) of the ZNF655 gene. This alteration results from a A to G substitution at nucleotide position 1322, causing the lysine (K) at amino acid position 441 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	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.49	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.52	N;.;.;N
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.053
Sift	Benign	0.034	D;T;T;D
Sift4G	Benign	0.068	T;T;T;T
Polyphen		0.90	P;P;P;P
Vest4		0.070
MutPred		0.45		Loss of methylation at K406 (P = 0.0032);.;.;Loss of methylation at K406 (P = 0.0032);
MVP		0.040
MPC		0.14
ClinPred		0.72	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.0099

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: rs1443966918; hg19: chr7-99170948;