chr19-56574400-G-A

Position:

• chr19-56574400-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000330619.13(ZNF470):​c.67G>A​(p.Val23Met) 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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V23L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF470 ENST00000330619.13 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.762

Genes affected

ZNF470 (HGNC:22220): (zinc finger protein 470) 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. Located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF470	NM_001001668.4	c.67G>A	p.Val23Met	missense_variant	4/6	ENST00000330619.13	NP_001001668.3
ZNF470	XM_047438804.1	c.67G>A	p.Val23Met	missense_variant	5/7		XP_047294760.1
ZNF470	XM_047438805.1	c.-87G>A		5_prime_UTR_variant	3/5		XP_047294761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF470	ENST00000330619.13	c.67G>A	p.Val23Met	missense_variant	4/6	1	NM_001001668.4	ENSP00000333223	P1
ZNF470	ENST00000601902.5	c.67G>A	p.Val23Met	missense_variant	4/6	1		ENSP00000471379
ZNF470	ENST00000391709.4	c.67G>A	p.Val23Met	missense_variant	2/4	5		ENSP00000375590	P1
ZNF470	ENST00000601059.1	n.609-238G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

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

Aug 30, 2021

The c.67G>A (p.V23M) alteration is located in exon 4 (coding exon 2) of the ZNF470 gene. This alteration results from a G to A substitution at nucleotide position 67, causing the valine (V) at amino acid position 23 to be replaced by a methionine (M). 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	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.0033	T;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.056
Sift	Benign	0.061	T;.;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.16
MutPred		0.72		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.099
MPC		0.015
ClinPred		0.065	T
GERP RS		-3.1
Varity_R		0.069
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10421285; hg19: chr19-57085769;