12-132926130-T-G

Position:

chr12-132926130-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_183238.4(ZNF605):c.1169A>C(p.Glu390Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,614,242 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 40 hom. )

Consequence

ZNF605
NM_183238.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.11

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005740434).

BP6

Variant 12-132926130-T-G is Benign according to our data. Variant chr12-132926130-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3197105.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00279 (425/152354) while in subpopulation EAS AF= 0.0247 (128/5186). AF 95% confidence interval is 0.0212. There are 3 homozygotes in gnomad4. There are 316 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF605	NM_183238.4 linkuse as main transcript	c.1169A>C	p.Glu390Ala	missense_variant	5/5	ENST00000360187.9	NP_899061.1
ZNF605	NM_001164715.2 linkuse as main transcript	c.1262A>C	p.Glu421Ala	missense_variant	5/5		NP_001158187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF605	ENST00000360187.9 linkuse as main transcript	c.1169A>C	p.Glu390Ala	missense_variant	5/5	1	NM_183238.4	ENSP00000353314		Q86T29-1
ZNF605	ENST00000392321.3 linkuse as main transcript	c.1262A>C	p.Glu421Ala	missense_variant	5/5	2		ENSP00000376135	P1	Q86T29-2
CHFR	ENST00000536932.5 linkuse as main transcript	c.-252+19491A>C		intron_variant		4		ENSP00000475247

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

424

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0244

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00424

AC:

184

AN:

43392

Hom.:

AF XY:

0.00453

AC XY:

101

AN XY:

22320

show subpopulations

Gnomad AFR exome

AF:

0.000205

Gnomad AMR exome

AF:

0.000167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0236

Gnomad SAS exome

AF:

0.00132

Gnomad FIN exome

AF:

0.0173

Gnomad NFE exome

AF:

0.000333

Gnomad OTH exome

AF:

0.00273

GnomAD4 exome

AF:

0.00205

AC:

3001

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

1484

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0303

Gnomad4 SAS exome

AF:

0.00110

Gnomad4 FIN exome

AF:

0.0226

Gnomad4 NFE exome

AF:

0.000331

Gnomad4 OTH exome

AF:

0.00190

GnomAD4 genome

AF:

0.00279

AC:

425

AN:

152354

Hom.:

Cov.:

AF XY:

0.00424

AC XY:

316

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0247

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0240

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000821

Hom.:

Bravo

AF:

0.00102

ExAC

AF:

0.000277

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

0.89

D;D

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.018

B;.

Vest4

0.28

MutPred

0.50

Loss of solvent accessibility (P = 0.0224);.;

MVP

0.43

ClinPred

0.081

GERP RS

2.5

Varity_R

0.38

gMVP

0.035

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