chr19-51993481-C-T

Variant names:

• chr19-51993481-C-T
• rs781201122
• NM_001199324.2:c.1628G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001199324.2(ZNF615):​c.1628G>A​(p.Arg543Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: ZNF615 NM_001199324.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.225
• Publications: 11 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2228432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF615	NM_001199324.2	c.1628G>A	p.Arg543Gln	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.1628G>A	p.Arg543Gln	missense_variant	Exon 7 of 7	1	NM_001199324.2	ENSP00000471041.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151914 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251438 AF XY: 0.0000294

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461850 Hom.: 0 Cov.: 37 AF XY: 0.0000550 AC XY: 40 AN XY: 727226

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1112004

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 151914 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74216

African (AFR) AF: 0.0000726 AC: 3 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1628G>A (p.R543Q) 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 1628, causing the arginine (R) at amino acid position 543 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.036	T;.;T;.;.;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.0069
FATHMM_MKL	Benign	0.00011	N
LIST_S2	Benign	0.18	.;.;T;T;.;T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;L;.;.;.;.
PhyloP100		-0.23
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	.;.;D;D;.;.;.
REVEL	Benign	0.091
Sift	Uncertain	0.017	.;.;D;D;.;.;.
Sift4G	Uncertain	0.047	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.;D
Vest4		0.22
MVP		0.42
MPC		0.27
ClinPred		0.79	D
GERP RS		3.1
Varity_R		0.30
gMVP		0.038
Mutation Taster		=97/3	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: rs781201122; hg19: chr19-52496734; COSMIC: COSV65032289; COSMIC: COSV65032289;