chr19-51993284-A-G

Variant names:

• chr19-51993284-A-G
• rs1231035899
• NM_001199324.2:c.1825T>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.1825T>C​(p.Cys609Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 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. C609G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF615 NM_001199324.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.17
• 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, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF615	NM_001199324.2	c.1825T>C	p.Cys609Arg	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.1825T>C	p.Cys609Arg	missense_variant	Exon 7 of 7	1	NM_001199324.2	ENSP00000471041.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251396 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 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: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 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: 0.00 AC: 0 AN: 1112000

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.21	.;.;T;T;.;T;T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.1	H;.;H;.;.;.;.
PhyloP100		8.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-9.9	.;.;D;D;.;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;.;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.;D
Vest4		0.61
MutPred		0.73		Gain of disorder (P = 0.0401);.;Gain of disorder (P = 0.0401);.;.;.;.;
MVP		0.90
MPC		0.31
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.93
gMVP		0.24
Mutation Taster		=91/9	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: rs1231035899; hg19: chr19-52496537;