X-135359991-T-C

Variant names:

• chrX-135359991-T-C
• rs1569498095
• NM_152695.6:c.659T>C

Variant summary

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

The NM_152695.6(ZNF449):​c.659T>C​(p.Leu220Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000935 in 1,069,751 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
• Consequence: ZNF449 NM_152695.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.111
• Publications: 0 publications found

Genes affected

ZNF449 (HGNC:21039): (zinc finger protein 449) This gene encodes a nuclear protein that likely functions as a transcription factor. The protein includes an N-terminal SCAN domain, and seven C2H2-type zinc finger motifs. [provided by RefSeq, May 2010]

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=0.2986114).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152695.6. 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
	ZNF449	NM_152695.6	MANE Select	c.659T>C	p.Leu220Pro	missense	Exon 4 of 5	NP_689908.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF449	ENST00000339249.5	TSL:1 MANE Select	c.659T>C	p.Leu220Pro	missense	Exon 4 of 5	ENSP00000339585.4	Q6P9G9-1
	ZNF449	ENST00000850984.1		c.659T>C	p.Leu220Pro	missense	Exon 4 of 5	ENSP00000521066.1
	ZNF449	ENST00000887114.1		c.659T>C	p.Leu220Pro	missense	Exon 4 of 5	ENSP00000557173.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.35e-7 AC: 1 AN: 1069751 Hom.: 0 Cov.: 25 AF XY: 0.00000295 AC XY: 1 AN XY: 338739

African (AFR) AF: 0.00 AC: 0 AN: 25465

American (AMR) AF: 0.00 AC: 0 AN: 33256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18933

East Asian (EAS) AF: 0.00 AC: 0 AN: 29968

South Asian (SAS) AF: 0.00 AC: 0 AN: 51677

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3987

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 821012

Other (OTH) AF: 0.0000222 AC: 1 AN: 45079

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Short stature (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.11
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.072
Sift	Benign	0.35	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.79
MutPred		0.49		Loss of stability (P = 0.039)
MVP		0.43
MPC		1.2
ClinPred		0.12	T
GERP RS		2.2
Varity_R		0.17
gMVP		0.64
Mutation Taster		=70/30	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: rs1569498095; hg19: chrX-134493916;