chr19-51993067-T-G

Variant names:

• chr19-51993067-T-G
• rs932156482
• NM_001199324.2:c.2042A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001199324.2(ZNF615):​c.2042A>C​(p.His681Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H681R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF615 NM_001199324.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

Genes affected

ZNF615 (HGNC:24740): (zinc finger protein 615) Predicted to enable DNA-binding transcription activator 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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF615	NM_001199324.2	c.2042A>C	p.His681Pro	missense_variant	Exon 7 of 7	ENST00000598071.6	NP_001186253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF615	ENST00000598071.6	c.2042A>C	p.His681Pro	missense_variant	Exon 7 of 7	1	NM_001199324.2	ENSP00000471041.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;.;T;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.73	.;.;T;T;.;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.7	H;.;H;.;.;.;.
PhyloP100		3.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.5	.;.;D;D;.;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	.;.;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.;D
Vest4		0.60
MutPred		0.83		Gain of phosphorylation at T669 (P = 0.083);.;Gain of phosphorylation at T669 (P = 0.083);.;.;.;.;
MVP		0.85
MPC		0.30
ClinPred		0.98	D
GERP RS		0.98
Varity_R		0.58
gMVP		0.21
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs932156482; hg19: chr19-52496320;