NM_018260.3:c.227T>G

Variant names:

• chr19-52582286-T-G
• rs779203279
• NM_018260.3:c.227T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_018260.3(ZNF701):​c.227T>G​(p.Ile76Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,470 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: ZNF701 NM_018260.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.33
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02767533).
• BP6: Variant 19-52582286-T-G is Benign according to our data. Variant chr19-52582286-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2459620.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF701	NM_018260.3	c.227T>G	p.Ile76Arg	missense_variant	Exon 4 of 4	ENST00000391785.8	NP_060730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF701	ENST00000391785.8	c.227T>G	p.Ile76Arg	missense_variant	Exon 4 of 4	1	NM_018260.3	ENSP00000375662.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250884 AF XY: 0.0000295

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1461344 Hom.: 0 Cov.: 31 AF XY: 0.0000592 AC XY: 43 AN XY: 726934

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000756 AC: 84 AN: 1111716

Other (OTH) AF: 0.0000828 AC: 5 AN: 60372

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74310

African (AFR) AF: 0.0000724 AC: 3 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

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

Alfa AF: 0.0000966 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 01, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.045
DANN	Benign	0.14
DEOGEN2	Benign	0.0016	.;T;.;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.13	T;.;T;T
M_CAP	Benign	0.00092	T
MetaRNN	Benign	0.028	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.7	N;.;.;.
PhyloP100		-1.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	4.8	N;N;.;N
REVEL	Benign	0.012
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;T;T
Vest4		0.10
MutPred		0.38		.;Gain of disorder (P = 0.0159);Gain of disorder (P = 0.0159);Gain of disorder (P = 0.0159);
MVP		0.12
MPC		0.050
ClinPred		0.057	T
GERP RS		-4.2
Varity_R		0.034
gMVP		0.022
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs779203279; hg19: chr19-53085539; COSMIC: COSV56525952; COSMIC: COSV56525952;