10-43608656-A-C

Position:

• chr10-43608656-A-C

Variant summary

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

The NM_145312.4(ZNF485):​c.67A>C​(p.Ile23Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF485 NM_145312.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.673

Genes affected

ZNF485 (HGNC:23440): (zinc finger protein 485) Predicted to enable DNA-binding transcription activator 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]

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=0.06534284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF485	NM_145312.4	c.67A>C	p.Ile23Leu	missense_variant	3/5	ENST00000361807.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF485	ENST00000361807.8	c.67A>C	p.Ile23Leu	missense_variant	3/5	1	NM_145312.4	P1
ZNF485	ENST00000374435.3	c.67A>C	p.Ile23Leu	missense_variant	3/5	1		P1
ZNF485	ENST00000430885.5	c.67A>C	p.Ile23Leu	missense_variant	3/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 17, 2023

The c.67A>C (p.I23L) alteration is located in exon 3 (coding exon 2) of the ZNF485 gene. This alteration results from a A to C substitution at nucleotide position 67, causing the isoleucine (I) at amino acid position 23 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.0083	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.030
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;T;D
Polyphen		0.0	B;.;B
Vest4		0.15
MutPred		0.50		Gain of catalytic residue at I23 (P = 0.0055);Gain of catalytic residue at I23 (P = 0.0055);Gain of catalytic residue at I23 (P = 0.0055);
MVP		0.12
MPC		0.12
ClinPred		0.042	T
GERP RS		-5.9
Varity_R		0.26
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr10-44104104;