chr19-52369969-C-G

Variant names:

• chr19-52369969-C-G
• rs1193136772
• NM_001145434.2:c.4C>G

Variant summary

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

The NM_001145434.2(ZNF880):​c.4C>G​(p.Leu2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,399,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: ZNF880 NM_001145434.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.209

Genes affected

ZNF880 (HGNC:37249): (zinc finger protein 880) 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. Predicted to be active 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 rank	MANE	Protein	UniProt
ZNF880	NM_001145434.2	c.4C>G	p.Leu2Val	missense_variant	Exon 1 of 4	ENST00000422689.3	NP_001138906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF880	ENST00000422689.3	c.4C>G	p.Leu2Val	missense_variant	Exon 1 of 4	2	NM_001145434.2	ENSP00000406318.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000500 AC: 7 AN: 1399400 Hom.: 0 Cov.: 31 AF XY: 0.00000580 AC XY: 4 AN XY: 690212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4C>G (p.L2V) alteration is located in exon 1 (coding exon 1) of the ZNF880 gene. This alteration results from a C to G substitution at nucleotide position 4, causing the leucine (L) at amino acid position 2 to be replaced by a valine (V). 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	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.9
DANN	Benign	0.96
DEOGEN2	Benign	0.0031	.;.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.53	.;T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.92	.;.;L;.;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;.;N;.;N
REVEL	Benign	0.011
Sift	Uncertain	0.0020	D;.;D;.;T
Sift4G	Uncertain	0.048	D;D;T;T;T
Polyphen		0.047	.;.;.;.;B
Vest4		0.067
MutPred		0.44		Loss of stability (P = 0.0718);Loss of stability (P = 0.0718);Loss of stability (P = 0.0718);Loss of stability (P = 0.0718);Loss of stability (P = 0.0718);
MVP		0.088
MPC		0.14
ClinPred		0.36	T
GERP RS		-0.89
Varity_R		0.069
gMVP		0.025

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1193136772; hg19: chr19-52873222;