12-6672461-T-C

Variant names:

• chr12-6672461-T-C
• rs1951865846
• NM_001385745.1:c.1076A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001385745.1(ZNF384):​c.1076A>G​(p.Asn359Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N359T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ZNF384 NM_001385745.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.99
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385745.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF384	NM_001385745.1	MANE Select	c.1076A>G	p.Asn359Ser	missense	Exon 9 of 12	NP_001372674.1	A0A804HJE2
	ZNF384	NM_001385743.1		c.1076A>G	p.Asn359Ser	missense	Exon 9 of 12	NP_001372672.1	A0A804HJE2
	ZNF384	NM_001385744.1		c.1076A>G	p.Asn359Ser	missense	Exon 9 of 12	NP_001372673.1	A0A804HJE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF384	ENST00000683879.1	MANE Select	c.1076A>G	p.Asn359Ser	missense	Exon 9 of 12	ENSP00000507462.1	A0A804HJE2
	ZNF384	ENST00000355772.8	TSL:1	c.746+755A>G		intron	N/A	ENSP00000348018.4	Q8TF68-3
	ZNF384	ENST00000710399.1		c.1127A>G	p.Asn376Ser	missense	Exon 9 of 12	ENSP00000518253.1	A0AA34QVS9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0050	N
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.29
Sift	Benign	0.039	D
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.55		Gain of catalytic residue at K324 (P = 0.0044)
MVP		0.26
MPC		1.0
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.21
gMVP		0.37
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs1951865846; hg19: chr12-6781627;