chr19-11780584-T-C

Position:

• chr19-11780584-T-C

Variant summary

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

The NM_152355.3(ZNF441):​c.760T>C​(p.Cys254Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ZNF441 NM_152355.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

Genes affected

ZNF441 (HGNC:20875): (zinc finger protein 441) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active 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
ZNF441	NM_152355.3	c.760T>C	p.Cys254Arg	missense_variant	4/4	ENST00000357901.5	NP_689568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF441	ENST00000357901.5	c.760T>C	p.Cys254Arg	missense_variant	4/4	3	NM_152355.3	ENSP00000350576.4
ZNF441	ENST00000409902.5	n.*689T>C		non_coding_transcript_exon_variant	5/5	2		ENSP00000386658.2
ZNF441	ENST00000409902.5	n.*689T>C		3_prime_UTR_variant	5/5	2		ENSP00000386658.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461858 Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14 AN XY: 727220

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: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Jul 26, 2022

The c.760T>C (p.C254R) alteration is located in exon 4 (coding exon 4) of the ZNF441 gene. This alteration results from a T to C substitution at nucleotide position 760, causing the cysteine (C) at amino acid position 254 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.077	T
M_CAP	Benign	0.0038	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	4.4	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-11	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.17
MutPred		0.65		Gain of MoRF binding (P = 0.0194);
MVP		0.89
MPC		1.4
ClinPred		1.0	D
GERP RS		1.0
Varity_R		0.44
gMVP		0.15

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: rs965723578; hg19: chr19-11891399;