12-132927160-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_183238.4(ZNF605):c.139G>A(p.Val47Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,544,688 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ZNF605 NM_183238.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0640

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026896238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF605	NM_183238.4	c.139G>A	p.Val47Ile	missense_variant, splice_region_variant	5/5	ENST00000360187.9
ZNF605	NM_001164715.2	c.232G>A	p.Val78Ile	missense_variant, splice_region_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF605	ENST00000360187.9	c.139G>A	p.Val47Ile	missense_variant, splice_region_variant	5/5	1	NM_183238.4
ZNF605	ENST00000392321.3	c.232G>A	p.Val78Ile	missense_variant, splice_region_variant	5/5	2		P1
CHFR	ENST00000536932.5	c.-252+18461G>A		intron_variant		4
ZNF605	ENST00000331711.11	n.350G>A		splice_region_variant, non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151820 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000251 AC: 35 AN: 1392750 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 18 AN XY: 689772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000867

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151938 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74228

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

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

Mar 24, 2023

The c.232G>A (p.V78I) 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 232, causing the valine (V) at amino acid position 78 to be replaced by an isoleucine (I). 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	0.084
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	13
Dann	Benign	0.82
DEOGEN2	Benign	0.0091	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.034	T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.16	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.047
Sift	Benign	0.82	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.0010	B;.
Vest4		0.071
MutPred		0.56		Loss of catalytic residue at V47 (P = 0.1222);.;
MVP		0.12
ClinPred		0.030	T
GERP RS		1.3
Varity_R		0.026
gMVP		0.032

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: rs973659429; hg19: chr12-133503746;