12-132927030-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_183238.4(ZNF605):c.269T>C(p.Leu90Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 1,609,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

ZNF605
NM_183238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.826

Variant links:

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]

ZNF605 links:

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]

CHFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08389005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF605	NM_183238.4 linkuse as main transcript	c.269T>C	p.Leu90Pro	missense_variant	5/5	ENST00000360187.9
ZNF605	NM_001164715.2 linkuse as main transcript	c.362T>C	p.Leu121Pro	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF605	ENST00000360187.9 linkuse as main transcript	c.269T>C	p.Leu90Pro	missense_variant	5/5	1	NM_183238.4		Q86T29-1
ZNF605	ENST00000392321.3 linkuse as main transcript	c.362T>C	p.Leu121Pro	missense_variant	5/5	2		P1	Q86T29-2
CHFR	ENST00000536932.5 linkuse as main transcript	c.-252+18591T>C		intron_variant		4
ZNF605	ENST00000331711.11 linkuse as main transcript	n.480T>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000434

AC:

632

AN:

1457556

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

300

AN XY:

725286

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000542

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000230

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000249

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.362T>C (p.L121P) alteration is located in exon 5 (coding exon 4) of the ZNF605 gene. This alteration results from a T to C substitution at nucleotide position 362, causing the leucine (L) at amino acid position 121 to be replaced by a proline (P). 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

-0.31

BayesDel_noAF

Benign

-0.68

Cadd

Benign

6.4

Dann

Benign

0.52

DEOGEN2

Benign

0.0099

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.010

T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.084

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.10

Sift

Benign

0.24

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0030

B;.

Vest4

0.071

MutPred

0.48

Loss of catalytic residue at L90 (P = 0.0072);.;

MVP

0.25

ClinPred

0.096

GERP RS

2.5

Varity_R

0.14

gMVP

0.051

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over