19-43872965-C-G

Position:

• chr19-43872965-C-G

Variant summary

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

The NM_001033719.3(ZNF404):​c.1249G>C​(p.Gly417Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF404 NM_001033719.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

ZNF404 (HGNC:19417): (zinc finger protein 404) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [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
ZNF404	NM_001033719.3	c.1249G>C	p.Gly417Arg	missense_variant	3/3	ENST00000587539.2	NP_001028891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF404	ENST00000587539.2	c.1249G>C	p.Gly417Arg	missense_variant	3/3	5	NM_001033719.3	ENSP00000466051	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453330 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 722210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

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 17, 2024

The c.1249G>C (p.G417R) alteration is located in exon 3 (coding exon 3) of the ZNF404 gene. This alteration results from a G to C substitution at nucleotide position 1249, causing the glycine (G) at amino acid position 417 to be replaced by an arginine (R). 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	0.31
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.37	T
REVEL	Benign	0.13
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;.
Vest4		0.32
MutPred		0.65		Gain of MoRF binding (P = 0.0294);.;
MVP		0.55
MPC		0.52
ClinPred		0.72	D
GERP RS		1.1
Varity_R		0.11
gMVP		0.042

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

LitVar

Other links and lift over

dbSNP: rs1018761356; hg19: chr19-44377117;