rs760978147

Variant names:

• chr19-52574161-A-C
• rs760978147
• NM_018260.3:c.14A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018260.3(ZNF701):​c.14A>C​(p.Gln5Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF701 NM_018260.3 missense, splice_region
• Scores: Splicing: ADA: 0.5985
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.541
• Publications: 0 publications found

Genes affected

ZNF701 (HGNC:25597): (zinc finger protein 701) 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 active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3552512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF701	NM_018260.3	c.14A>C	p.Gln5Pro	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000391785.8	NP_060730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF701	ENST00000391785.8	c.14A>C	p.Gln5Pro	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_018260.3	ENSP00000375662.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457874 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725388

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109560

Other (OTH) AF: 0.00 AC: 0 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212A>C (p.Q71P) alteration is located in exon 3 (coding exon 2) of the ZNF701 gene. This alteration results from a A to C substitution at nucleotide position 212, causing the glutamine (Q) at amino acid position 71 to be replaced by a proline (P). 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	0.097
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	.;.;T;.;T
Eigen	Benign	0.028
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.15	T;T;.;T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	.;M;.;.;.
PhyloP100		0.54
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-4.1	.;D;D;.;D
REVEL	Benign	0.065
Sift	Uncertain	0.0010	.;D;D;.;D
Sift4G	Uncertain	0.017	D;D;D;D;D
Vest4		0.38, 0.48
MutPred		0.61		.;.;Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);
MVP		0.34
MPC		0.56
ClinPred		0.91	D
GERP RS		1.5
Varity_R		0.44
gMVP		0.26
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.60
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.050		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: rs760978147; hg19: chr19-53077414;