19-19891738-C-G

Variant names:

• chr19-19891738-C-G
• rs371659973
• NM_021047.3:c.491C>G

Variant summary

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

The NM_021047.3(ZNF253):​c.491C>G​(p.Thr164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T164K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF253 NM_021047.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 0 publications found

Genes affected

ZNF253 (HGNC:13497): (zinc finger protein 253) 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, DNA-templated. Predicted to be located 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=0.046391666).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021047.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF253	NM_021047.3	MANE Select	c.491C>G	p.Thr164Arg	missense	Exon 4 of 4	NP_066385.2	O75346-1
	ZNF253	NM_001331133.1		c.299C>G	p.Thr100Arg	missense	Exon 3 of 3	NP_001318062.1	O75346
	ZNF253	NM_001331134.1		c.263C>G	p.Thr88Arg	missense	Exon 2 of 2	NP_001318063.1	O75346-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF253	ENST00000589717.2	TSL:1 MANE Select	c.491C>G	p.Thr164Arg	missense	Exon 4 of 4	ENSP00000468720.1	O75346-1
	ZNF253	ENST00000355650.4	TSL:1	c.263C>G	p.Thr88Arg	missense	Exon 2 of 2	ENSP00000347868.4	O75346-2
	ZNF253	ENST00000937512.1		c.428C>G	p.Thr143Arg	missense	Exon 4 of 4	ENSP00000607571.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461742 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.23
DANN	Benign	0.58
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00010	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.75	N
PhyloP100		-2.0
PrimateAI	Benign	0.37	T
REVEL	Benign	0.023
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.093
MutPred		0.39		Gain of MoRF binding (P = 0.0262)
MVP		0.14
MPC		0.12
ClinPred		0.036	T
GERP RS		-2.8
Varity_R		0.059
gMVP		0.014
Mutation Taster		=100/0	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: rs371659973; hg19: chr19-20002547;