19-22180306-G-T

Position:

• chr19-22180306-G-T

Variant summary

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

The NM_001001411.3(ZNF676):​c.1411C>A​(p.His471Asn) variant causes a missense change. 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: 33)
• Consequence: ZNF676 NM_001001411.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

Genes affected

ZNF676 (HGNC:20429): (zinc finger protein 676) 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, DNA-templated. Predicted to be located in nucleus. [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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF676	NM_001001411.3	c.1411C>A	p.His471Asn	missense_variant	3/3	ENST00000397121.3	NP_001001411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF676	ENST00000397121.3	c.1411C>A	p.His471Asn	missense_variant	3/3	2	NM_001001411.3	ENSP00000380310.1
ZNF676	ENST00000650058.1	c.1507C>A	p.His503Asn	missense_variant	4/4			ENSP00000497897.1

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 18, 2024

The c.1411C>A (p.H471N) alteration is located in exon 3 (coding exon 3) of the ZNF676 gene. This alteration results from a C to A substitution at nucleotide position 1411, causing the histidine (H) at amino acid position 471 to be replaced by an asparagine (N). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.13
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.32	.;T
M_CAP	Benign	0.0029	T
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.2	D;.
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.27
MutPred		0.93		Gain of MoRF binding (P = 0.1006);.;
MVP		0.65
MPC		0.19
ClinPred		0.99	D
GERP RS		0.81
Varity_R		0.42
gMVP		0.013

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: rs920444216; hg19: chr19-22363108;