19-52950042-C-G

Variant names:

• chr19-52950042-C-G
• rs878995040
• NM_001202457.3:c.1733G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001202457.3(ZNF816):​c.1733G>C​(p.Gly578Ala) 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 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ZNF816 NM_001202457.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.25

Genes affected

ZNF816 (HGNC:26995): (zinc finger protein 816) 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 integral component of membrane. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF816-ZNF321P (HGNC:38879): (ZNF816-ZNF321P readthrough) This locus represents naturally occurring read-through transcription between the zinc finger protein 816 (ZNF816) gene and the zinc finger protein 321 (ZNF321) pseudogene on chromosome 19. The read-through transcript encodes a KRAB domain-containing protein that shares sequence identity with the upstream gene product, but it contains a distinct C-terminus encoded by exon structure from the downstream pseudogene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06421569).
• BP6: Variant 19-52950042-C-G is Benign according to our data. Variant chr19-52950042-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2288960.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF816	NM_001202457.3	c.1733G>C	p.Gly578Ala	missense_variant	Exon 4 of 4	ENST00000444460.7	NP_001189386.1
ZNF816	NM_001031665.4	c.1733G>C	p.Gly578Ala	missense_variant	Exon 5 of 5		NP_001026835.1
ZNF816	NM_001202456.3	c.1733G>C	p.Gly578Ala	missense_variant	Exon 4 of 4		NP_001189385.1
ZNF816-ZNF321P	NM_001202473.2	c.190+2709G>C		intron_variant	Intron 3 of 3		NP_001189402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF816	ENST00000444460.7	c.1733G>C	p.Gly578Ala	missense_variant	Exon 4 of 4	1	NM_001202457.3	ENSP00000403266.2
ZNF816	ENST00000357666.8	c.1733G>C	p.Gly578Ala	missense_variant	Exon 5 of 5	1		ENSP00000350295.4
ZNF816-ZNF321P	ENST00000391777.3	c.190+2709G>C		intron_variant	Intron 3 of 3	2		ENSP00000375656.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251124 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135766

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461674 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727130

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 11, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.48
DANN	Benign	0.73
DEOGEN2	Benign	0.00041	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.28	.;T
M_CAP	Benign	0.00051	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.52	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.64	N;N
REVEL	Benign	0.018
Sift	Benign	0.039	D;D
Sift4G	Benign	0.084	T;T
Polyphen		0.0	B;B
Vest4		0.024
MutPred		0.49		Loss of relative solvent accessibility (P = 0.114);Loss of relative solvent accessibility (P = 0.114);
MVP		0.081
MPC		0.083
ClinPred		0.043	T
GERP RS		-0.63
Varity_R		0.034
gMVP		0.0099

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: rs878995040; hg19: chr19-53453295;