19-44085746-C-A

Variant names:

• chr19-44085746-C-A
• rs1377992333
• NM_001037813.4:c.268C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001037813.4(ZNF284):​c.268C>A​(p.Pro90Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ZNF284 NM_001037813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.93

Genes affected

ZNF284 (HGNC:13078): (zinc finger protein 284) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267022 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05271551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF284	NM_001037813.4	c.268C>A	p.Pro90Thr	missense_variant	Exon 5 of 5	ENST00000421176.4	NP_001032902.1
ZNF284	XM_011526907.4	c.268C>A	p.Pro90Thr	missense_variant	Exon 5 of 5		XP_011525209.1
ZNF284	XM_011526908.4	c.268C>A	p.Pro90Thr	missense_variant	Exon 6 of 6		XP_011525210.1
ZNF284	XM_024451486.2	c.268C>A	p.Pro90Thr	missense_variant	Exon 5 of 5		XP_024307254.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF284	ENST00000421176.4	c.268C>A	p.Pro90Thr	missense_variant	Exon 5 of 5	1	NM_001037813.4	ENSP00000411032.2
ENSG00000267022	ENST00000591793.1	n.*314C>A		non_coding_transcript_exon_variant	Exon 11 of 11	2		ENSP00000467018.1
ENSG00000267022	ENST00000591793.1	n.*314C>A		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000467018.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461398 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 726974

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: 0.0000315

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000620 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>A (p.P90T) alteration is located in exon 5 (coding exon 4) of the ZNF284 gene. This alteration results from a C to A substitution at nucleotide position 268, causing the proline (P) at amino acid position 90 to be replaced by a threonine (T). 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	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.9
DANN	Benign	0.97
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.96	L
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.032
Sift	Benign	0.12	T
Sift4G	Benign	0.43	T
Polyphen		0.070	B
Vest4		0.036
MVP		0.092
MPC		0.038
ClinPred		0.063	T
GERP RS		-2.1
Varity_R		0.058
gMVP		0.026

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1377992333; hg19: chr19-44589899;