chr19-52950232-C-G

Position:

• chr19-52950232-C-G

Variant summary

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

The NM_001202457.3(ZNF816):​c.1543G>C​(p.Asp515His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF816 NM_001202457.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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:):

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=0.20750412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF816	NM_001202457.3	c.1543G>C	p.Asp515His	missense_variant	4/4	ENST00000444460.7	NP_001189386.1
ZNF816-ZNF321P	NM_001202473.2	c.190+2519G>C		intron_variant			NP_001189402.1
ZNF816	NM_001031665.4	c.1543G>C	p.Asp515His	missense_variant	5/5		NP_001026835.1
ZNF816	NM_001202456.3	c.1543G>C	p.Asp515His	missense_variant	4/4		NP_001189385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF816	ENST00000444460.7	c.1543G>C	p.Asp515His	missense_variant	4/4	1	NM_001202457.3	ENSP00000403266	P1
ZNF816	ENST00000357666.8	c.1543G>C	p.Asp515His	missense_variant	5/5	1		ENSP00000350295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727220

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jun 05, 2023

The c.1543G>C (p.D515H) alteration is located in exon 5 (coding exon 3) of the ZNF816 gene. This alteration results from a G to C substitution at nucleotide position 1543, causing the aspartic acid (D) at amino acid position 515 to be replaced by a histidine (H). 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	0.27
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.072
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.17
MutPred		0.51		Gain of MoRF binding (P = 0.0389);Gain of MoRF binding (P = 0.0389);
MVP		0.17
MPC		0.44
ClinPred		0.89	D
GERP RS		1.9
Varity_R		0.11
gMVP		0.044

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: rs2083443217; hg19: chr19-53453485;