X-135349306-T-A

Position:

• chrX-135349306-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152695.6(ZNF449):​c.551T>A​(p.Leu184Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZNF449 NM_152695.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.568

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2950849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF449	NM_152695.6	c.551T>A	p.Leu184Gln	missense_variant	3/5	ENST00000339249.5	NP_689908.3
ZNF449	XM_047441914.1	c.551T>A	p.Leu184Gln	missense_variant	3/5		XP_047297870.1
ZNF449	XM_017029351.2	c.206T>A	p.Leu69Gln	missense_variant	4/6		XP_016884840.1
ZNF449	XM_047441915.1	c.206T>A	p.Leu69Gln	missense_variant	4/6		XP_047297871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF449	ENST00000339249.5	c.551T>A	p.Leu184Gln	missense_variant	3/5	1	NM_152695.6	ENSP00000339585.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.551T>A (p.L184Q) alteration is located in exon 3 (coding exon 2) of the ZNF449 gene. This alteration results from a T to A substitution at nucleotide position 551, causing the leucine (L) at amino acid position 184 to be replaced by a glutamine (Q). 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	0.088
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.033	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.13
Sift	Benign	0.15	T
Sift4G	Uncertain	0.052	T
Polyphen		0.84	P
Vest4		0.22
MutPred		0.73		Loss of stability (P = 0.0104);
MVP		0.52
MPC		1.0
ClinPred		0.28	T
GERP RS		1.9
Varity_R		0.087
gMVP		0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-134483231;