19-20624884-A-T

Variant summary

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

The NM_001076675.3(ZNF626):c.993T>A(p.His331Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ZNF626 NM_001076675.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.470

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF626	NM_001076675.3	c.993T>A	p.His331Gln	missense_variant	4/4	ENST00000601440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF626	ENST00000601440.6	c.993T>A	p.His331Gln	missense_variant	4/4	4	NM_001076675.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250000 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461652 Hom.: 0 Cov.: 83 AF XY: 0.0000151 AC XY: 11 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Apr 07, 2022

The c.993T>A (p.H331Q) alteration is located in exon 4 (coding exon 4) of the ZNF626 gene. This alteration results from a T to A substitution at nucleotide position 993, causing the histidine (H) at amino acid position 331 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	0.91
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.38	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	N
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.23
MutPred		0.75		Loss of catalytic residue at K332 (P = 0.1278);Loss of catalytic residue at K332 (P = 0.1278);
MVP		0.86
MPC		0.31
ClinPred		0.42	T
GERP RS		0.90
Varity_R		0.31
gMVP		0.045

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: rs868987775; hg19: chr19-20807690;