12-6668103-T-C

Variant names:

• chr12-6668103-T-C
• rs201837928
• NM_001385745.1:c.1438A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001385745.1(ZNF384):​c.1438A>G​(p.Met480Val) variant causes a missense change. The variant allele was found at a frequency of 0.000268 in 1,593,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ZNF384 NM_001385745.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33

Genes affected

ZNF384 (HGNC:11955): (zinc finger protein 384) This gene encodes a C2H2-type zinc finger protein, which may function as a transcription factor. This gene also contains long CAG trinucleotide repeats that encode consecutive glutamine residues. The protein appears to bind and regulate the promoters of the extracellular matrix genes MMP1, MMP3, MMP7 and COL1A1. Studies in mouse suggest that nuclear matrix transcription factors (NP/NMP4) may be part of a general mechanical pathway that couples cell construction and function during extracellular matrix remodeling. Alternative splicing results in multiple transcript variants. Recurrent rearrangements of this gene with the Ewing's sarcoma gene, EWSR1 on chromosome 22, or with the TAF15 gene on chromosome 17, or with the TCF3 (E2A) gene on chromosome 19, have been observed in acute leukemia. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Apr 2011]

ENSG00000219410 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24347448).
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF384	NM_001385745.1	c.1438A>G	p.Met480Val	missense_variant	Exon 12 of 12	ENST00000683879.1	NP_001372674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF384	ENST00000683879.1	c.1438A>G	p.Met480Val	missense_variant	Exon 12 of 12		NM_001385745.1	ENSP00000507462.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000163 AC: 38 AN: 232436 Hom.: 0 AF XY: 0.000151 AC XY: 19 AN XY: 125532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000297

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 408 AN: 1441468 Hom.: 0 Cov.: 36 AF XY: 0.000253 AC XY: 181 AN XY: 714904

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.000188

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000334

Gnomad4 OTH exome AF: 0.000303

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152316 Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1345A>G (p.M449V) alteration is located in exon 11 (coding exon 9) of the ZNF384 gene. This alteration results from a A to G substitution at nucleotide position 1345, causing the methionine (M) at amino acid position 449 to be replaced by a valine (V). 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	0.30
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.23	.;T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.53	.;N;N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.17	.;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.90	P;D;D;D
Vest4		0.63
MVP		0.19
MPC		1.5
ClinPred		0.60	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.38

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: rs201837928; hg19: chr12-6777269;