chr19-58477326-G-C

Position:

• chr19-58477326-G-C

Variant summary

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

The NM_017908.4(ZNF446):​c.108G>C​(p.Glu36Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF446 NM_017908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.205

Genes affected

ZNF446 (HGNC:21036): (zinc finger protein 446) Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4	c.108G>C	p.Glu36Asp	missense_variant	2/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1	c.108G>C	p.Glu36Asp	missense_variant	1/6		NP_001291382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF446	ENST00000594369.6	c.108G>C	p.Glu36Asp	missense_variant	2/7	1	NM_017908.4	ENSP00000472802	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 09, 2021

The c.108G>C (p.E36D) alteration is located in exon 2 (coding exon 1) of the ZNF446 gene. This alteration results from a G to C substitution at nucleotide position 108, causing the glutamic acid (E) at amino acid position 36 to be replaced by an aspartic acid (D). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T;T;.;.;.
Eigen	Benign	0.097
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.71	T;T;T;T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.;M
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	.;.;.;.;N;.
REVEL	Benign	0.18
Sift	Benign	0.10	.;.;.;.;T;.
Sift4G	Uncertain	0.049	D;T;D;D;T;D
Polyphen		0.94	.;.;P;.;.;.
Vest4		0.34
MutPred		0.85		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.16
MPC		0.11
ClinPred		0.59	D
GERP RS		1.1
Varity_R		0.069
gMVP		0.21

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: chr19-58988693;