12-132926130-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.11

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 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 GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF605	NM_183238.4	c.1169A>C	p.Glu390Ala	missense_variant	5/5	ENST00000360187.9
ZNF605	NM_001164715.2	c.1262A>C	p.Glu421Ala	missense_variant	5/5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152236 Hom.: 3 Cov.: 33

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.: 4 AF XY: 0.00453 AC XY: 101 AN XY: 22320

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.: 40 Cov.: 32 AF XY: 0.00204 AC XY: 1484 AN XY: 727246

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.: 3 Cov.: 33 AF XY: 0.00424 AC XY: 316 AN XY: 74502

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.: 3

Bravo AF: 0.00102

ExAC AF: 0.000277 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs201757638; hg19: chr12-133502716; COSMIC: COSV59159489; COSMIC: COSV59159489;