X-135360458-C-A

Position:

• chrX-135360458-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152695.6(ZNF449):​c.939C>A​(p.His313Gln) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZNF449 NM_152695.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.00

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07550189).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF449	NM_152695.6	c.939C>A	p.His313Gln	missense_variant	5/5	ENST00000339249.5	NP_689908.3
ZNF449	XM_047441914.1	c.939C>A	p.His313Gln	missense_variant	5/5		XP_047297870.1
ZNF449	XM_017029351.2	c.594C>A	p.His198Gln	missense_variant	6/6		XP_016884840.1
ZNF449	XM_047441915.1	c.594C>A	p.His198Gln	missense_variant	6/6		XP_047297871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF449	ENST00000339249.5	c.939C>A	p.His313Gln	missense_variant	5/5	1	NM_152695.6	ENSP00000339585.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

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

Aug 12, 2021

The c.939C>A (p.H313Q) alteration is located in exon 5 (coding exon 4) of the ZNF449 gene. This alteration results from a C to A substitution at nucleotide position 939, causing the histidine (H) at amino acid position 313 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	0.23
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0060
DANN	Benign	0.70
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.048
Sift	Benign	0.094	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.085
MutPred		0.33		Loss of helix (P = 0.0626);
MVP		0.49
MPC		0.64
ClinPred		0.051	T
GERP RS		-5.1
Varity_R		0.14
gMVP		0.44

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-134494383;