19-20625402-T-C

Position:

• chr19-20625402-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001076675.3(ZNF626):​c.475A>G​(p.Asn159Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZNF626 NM_001076675.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.381

Genes affected

ZNF626 (HGNC:30461): (zinc finger protein 626) 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1332826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF626	NM_001076675.3	c.475A>G	p.Asn159Asp	missense_variant	4/4	ENST00000601440.6	NP_001070143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF626	ENST00000601440.6	c.475A>G	p.Asn159Asp	missense_variant	4/4	4	NM_001076675.3	ENSP00000469958	P1
ZNF626	ENST00000595405.1	c.247A>G	p.Asn83Asp	missense_variant	2/2	3		ENSP00000469566

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461772 Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 4 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Feb 28, 2024

The c.475A>G (p.N159D) alteration is located in exon 4 (coding exon 4) of the ZNF626 gene. This alteration results from a A to G substitution at nucleotide position 475, causing the asparagine (N) at amino acid position 159 to be replaced by an aspartic acid (D). 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	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.040	T;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	1.0	N
Sift4G	Uncertain	0.032	D;T;D
Polyphen		0.20	B;.;.
Vest4		0.093
MutPred		0.31		Loss of MoRF binding (P = 0.058);Loss of MoRF binding (P = 0.058);.;
MVP		0.44
MPC		0.048
ClinPred		0.20	T
GERP RS		0.90
Varity_R		0.22
gMVP		0.00090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1969815828; hg19: chr19-20808208;