rs1385976380

Variant names:

• chr19-52572312-C-T
• rs1385976380
• ENST00000301093.6:c.71C>T

Variant summary

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

The NM_018260.3(ZNF701):​c.-71-1765C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,167,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: ZNF701 NM_018260.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.947
• 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: 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=0.06474337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF701	NM_018260.3	c.-71-1765C>T		intron_variant	Intron 1 of 3	ENST00000391785.8	NP_060730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF701	ENST00000391785.8	c.-71-1765C>T		intron_variant	Intron 1 of 3	1	NM_018260.3	ENSP00000375662.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 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

GnomAD2 exomes AF: 0.00000795 AC: 1 AN: 125846 AF XY: 0.0000145

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: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000295 AC: 3 AN: 1015254 Hom.: 0 Cov.: 14 AF XY: 0.00000595 AC XY: 3 AN XY: 504300

African (AFR) AF: 0.00 AC: 0 AN: 21904

American (AMR) AF: 0.00 AC: 0 AN: 27522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15052

East Asian (EAS) AF: 0.00 AC: 0 AN: 12180

South Asian (SAS) AF: 0.00 AC: 0 AN: 73512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4158

European-Non Finnish (NFE) AF: 0.00000370 AC: 3 AN: 810922

Other (OTH) AF: 0.00 AC: 0 AN: 37408

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

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

African (AFR) AF: 0.00 AC: 0 AN: 41426

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71C>T (p.S24F) alteration is located in exon 2 (coding exon 1) of the ZNF701 gene. This alteration results from a C to T substitution at nucleotide position 71, causing the serine (S) at amino acid position 24 to be replaced by a phenylalanine (F). 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	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.00067	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.95
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.64	N;.;N
REVEL	Benign	0.064
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.16
MutPred		0.24		Loss of phosphorylation at S24 (P = 0.0435);Loss of phosphorylation at S24 (P = 0.0435);Loss of phosphorylation at S24 (P = 0.0435);
MVP		0.061
MPC		0.12
ClinPred		0.12	T
GERP RS		-0.32
Varity_R		0.16
gMVP		0.054
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: rs1385976380; hg19: chr19-53075565;