12-132926386-C-T

Variant summary

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

The NM_183238.4(ZNF605):c.913G>A(p.Gly305Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,892 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: 0.0000034 (0 hom.)
• Consequence: ZNF605 NM_183238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

Genes affected

ZNF605 (HGNC:28068): (zinc finger protein 605) 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]

CHFR (HGNC:20455): (checkpoint with forkhead and ring finger domains) This gene encodes an E3 ubiquitin-protein ligase required for the maintenance of the antephase checkpoint that regulates cell cycle entry into mitosis and, therefore, may play a key role in cell cycle progression and tumorigenesis. The encoded protein has an N-terminal forkhead-associated domain, a central RING-finger domain, and a cysteine-rich C-terminal region. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Mar 2014]

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=0.3558418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF605	NM_183238.4	c.913G>A	p.Gly305Arg	missense_variant	5/5	ENST00000360187.9
ZNF605	NM_001164715.2	c.1006G>A	p.Gly336Arg	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF605	ENST00000360187.9	c.913G>A	p.Gly305Arg	missense_variant	5/5	1	NM_183238.4
ZNF605	ENST00000392321.3	c.1006G>A	p.Gly336Arg	missense_variant	5/5	2		P1
CHFR	ENST00000536932.5	c.-252+19235G>A		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Dec 14, 2021

The c.1006G>A (p.G336R) alteration is located in exon 5 (coding exon 4) of the ZNF605 gene. This alteration results from a G to A substitution at nucleotide position 1006, causing the glycine (G) at amino acid position 336 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.060	T;T
Polyphen		1.0	D;.
Vest4		0.37
MutPred		0.57		Gain of solvent accessibility (P = 0.0037);.;
MVP		0.66
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.68
gMVP		0.029

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: chr12-133502972;