19-56574452-T-A

Position:

• chr19-56574452-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000330619.13(ZNF470):​c.119T>A​(p.Leu40Gln) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF470 ENST00000330619.13 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF470	NM_001001668.4	c.119T>A	p.Leu40Gln	missense_variant	4/6	ENST00000330619.13	NP_001001668.3
ZNF470	XM_047438804.1	c.119T>A	p.Leu40Gln	missense_variant	5/7		XP_047294760.1
ZNF470	XM_047438805.1	c.-35T>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.119T>A	p.Leu40Gln	missense_variant	4/6	1	NM_001001668.4	ENSP00000333223	P1
ZNF470	ENST00000601902.5	c.119T>A	p.Leu40Gln	missense_variant	4/6	1		ENSP00000471379
ZNF470	ENST00000391709.4	c.119T>A	p.Leu40Gln	missense_variant	2/4	5		ENSP00000375590	P1
ZNF470	ENST00000601059.1	n.609-186T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jan 02, 2024

The c.119T>A (p.L40Q) alteration is located in exon 4 (coding exon 2) of the ZNF470 gene. This alteration results from a T to A substitution at nucleotide position 119, causing the leucine (L) at amino acid position 40 to be replaced by a glutamine (Q). 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	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	.;T;D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.8	H;.;H
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.9	D;.;D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.78
MutPred		0.81		Gain of disorder (P = 0.1264);Gain of disorder (P = 0.1264);Gain of disorder (P = 0.1264);
MVP		0.67
MPC		0.10
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.87
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-57085821;