NM_018260.3:c.68A>C

Variant names:

• chr19-52575947-A-C
• rs529423985
• NM_018260.3:c.68A>C

Variant summary

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

The NM_018260.3(ZNF701):​c.68A>C​(p.Lys23Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 146,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. K23R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF701 NM_018260.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.18
• 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]

ENSG00000268886 (HGNC:):

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=0.21075207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF701	NM_018260.3	c.68A>C	p.Lys23Thr	missense_variant	Exon 3 of 4	ENST00000391785.8	NP_060730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF701	ENST00000391785.8	c.68A>C	p.Lys23Thr	missense_variant	Exon 3 of 4	1	NM_018260.3	ENSP00000375662.2

Frequencies

GnomAD3 genomes AF: 0.0000274 AC: 4 AN: 146070 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000102

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000897 AC: 2 AN: 222868 AF XY: 0.00000821

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000710

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000351 AC: 5 AN: 1424732 Hom.: 0 Cov.: 30 AF XY: 0.00000283 AC XY: 2 AN XY: 706648

African (AFR) AF: 0.0000947 AC: 3 AN: 31670

American (AMR) AF: 0.0000535 AC: 2 AN: 37376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24376

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.00 AC: 0 AN: 82056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095962

Other (OTH) AF: 0.00 AC: 0 AN: 58812

GnomAD4 genome AF: 0.0000274 AC: 4 AN: 146070 Hom.: 0 Cov.: 26 AF XY: 0.0000423 AC XY: 3 AN XY: 70844

African (AFR) AF: 0.000102 AC: 4 AN: 39066

American (AMR) AF: 0.00 AC: 0 AN: 14244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9900

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66816

Other (OTH) AF: 0.00 AC: 0 AN: 1954

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.266A>C (p.K89T) alteration is located in exon 4 (coding exon 3) of the ZNF701 gene. This alteration results from a A to C substitution at nucleotide position 266, causing the lysine (K) at amino acid position 89 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	.;.;T;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.051	T;T;.;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.66	.;N;.;.;.
PhyloP100		-1.2
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.5	.;D;D;.;D
REVEL	Benign	0.034
Sift	Benign	0.098	.;T;T;.;T
Sift4G	Uncertain	0.030	D;T;T;D;T
Vest4		0.32, 0.30
MutPred		0.54		.;.;Loss of methylation at K89 (P = 2e-04);Loss of methylation at K89 (P = 2e-04);Loss of methylation at K89 (P = 2e-04);
MVP		0.19
MPC		4.0
ClinPred		0.40	T
GERP RS		-0.51
Varity_R		0.10
gMVP		0.045
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: rs529423985; hg19: chr19-53079200;