19-51993400-C-T

Variant names:

• chr19-51993400-C-T
• rs762696316
• NM_001199324.2:c.1709G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001199324.2(ZNF615):​c.1709G>A​(p.Arg570Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,612,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R570W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ZNF615 NM_001199324.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.634
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024170816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF615	NM_001199324.2	c.1709G>A	p.Arg570Gln	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.1709G>A	p.Arg570Gln	missense_variant	Exon 7 of 7	1	NM_001199324.2	ENSP00000471041.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150646 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251392 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461824 Hom.: 0 Cov.: 37 AF XY: 0.0000138 AC XY: 10 AN XY: 727208

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111974

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150646 Hom.: 0 Cov.: 32 AF XY: 0.0000408 AC XY: 3 AN XY: 73536

African (AFR) AF: 0.0000490 AC: 2 AN: 40848

American (AMR) AF: 0.0000661 AC: 1 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67650

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1709G>A (p.R570Q) alteration is located in exon 7 (coding exon 5) of the ZNF615 gene. This alteration results from a G to A substitution at nucleotide position 1709, causing the arginine (R) at amino acid position 570 to be replaced by a glutamine (Q). 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	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Benign	0.49
DEOGEN2	Benign	0.00081	T;.;T;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.000030	N
LIST_S2	Benign	0.40	.;.;T;T;.;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.024	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.58	N;.;N;.;.;.;.
PhyloP100		-0.63
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.7	.;.;N;N;.;.;.
REVEL	Benign	0.091
Sift	Benign	1.0	.;.;T;T;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0020	B;B;B;.;B;.;B
Vest4		0.039
MutPred		0.50		Loss of MoRF binding (P = 0.0567);.;Loss of MoRF binding (P = 0.0567);.;.;.;.;
MVP		0.095
MPC		0.038
ClinPred		0.028	T
GERP RS		-1.9
Varity_R		0.044
gMVP		0.049
Mutation Taster		=99/1	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: rs762696316; hg19: chr19-52496653; COSMIC: COSV65033911; COSMIC: COSV65033911;