12-132927137-C-A

Position:

• chr12-132927137-C-A

Variant summary

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

The NM_183238.4(ZNF605):​c.162G>T​(p.Met54Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: ZNF605 NM_183238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.189

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=0.06452954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF605	NM_183238.4	c.162G>T	p.Met54Ile	missense_variant	5/5	ENST00000360187.9	NP_899061.1
ZNF605	NM_001164715.2	c.255G>T	p.Met85Ile	missense_variant	5/5		NP_001158187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF605	ENST00000360187.9	c.162G>T	p.Met54Ile	missense_variant	5/5	1	NM_183238.4	ENSP00000353314
ZNF605	ENST00000392321.3	c.255G>T	p.Met85Ile	missense_variant	5/5	2		ENSP00000376135	P1
CHFR	ENST00000536932.5	c.-252+18484G>T		intron_variant		4		ENSP00000475247
ZNF605	ENST00000331711.11	n.373G>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Mar 30, 2022

The c.255G>T (p.M85I) alteration is located in exon 5 (coding exon 4) of the ZNF605 gene. This alteration results from a G to T substitution at nucleotide position 255, causing the methionine (M) at amino acid position 85 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	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.8
DANN	Benign	0.62
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.13	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.15	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.024
Sift	Benign	0.39	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0	B;.
Vest4		0.14
MutPred		0.34		Loss of disorder (P = 0.0769);.;
MVP		0.25
ClinPred		0.028	T
GERP RS		1.8
Varity_R		0.049
gMVP		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr12-133503723;