18-35374118-C-T

Variant names:

• chr18-35374118-C-T
• rs137966135
• NM_001322286.2:c.175G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001322286.2(ZNF396):​c.175G>A​(p.Gly59Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ZNF396 NM_001322286.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.292
• Publications: 0 publications found

Genes affected

ZNF396 (HGNC:18824): (zinc finger protein 396) Enables protein heterodimerization activity; protein homodimerization activity; and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription, DNA-templated. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.016544431).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322286.2. 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
	ZNF396	NM_001322286.2	MANE Select	c.175G>A	p.Gly59Ser	missense	Exon 2 of 4	NP_001309215.1	Q96N95-1
	ZNF396	NM_001322290.2		c.175G>A	p.Gly59Ser	missense	Exon 3 of 5	NP_001309219.1	Q96N95-1
	ZNF396	NM_145756.3		c.175G>A	p.Gly59Ser	missense	Exon 2 of 5	NP_665699.1	Q96N95-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF396	ENST00000589332.7	TSL:1 MANE Select	c.175G>A	p.Gly59Ser	missense	Exon 2 of 4	ENSP00000466500.1	Q96N95-1
	ZNF396	ENST00000306346.5	TSL:1	c.175G>A	p.Gly59Ser	missense	Exon 2 of 5	ENSP00000302310.1	Q96N95-3
	ZNF396	ENST00000586687.5	TSL:1	c.175G>A	p.Gly59Ser	missense	Exon 2 of 3	ENSP00000467275.1	Q96N95-2

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 251468 AF XY: 0.000162

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000142 AC XY: 103 AN XY: 727248

African (AFR) AF: 0.00185 AC: 62 AN: 33480

American (AMR) AF: 0.000246 AC: 11 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: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000121 AC: 135 AN: 1112012

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74494

African (AFR) AF: 0.00202 AC: 84 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000501 Hom.: 0

Bravo AF: 0.000604

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.29
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.044
Sift	Benign	0.46	T
Sift4G	Benign	0.37	T
Polyphen		0.57	P
Vest4		0.21
MVP		0.16
MPC		0.54
ClinPred		0.032	T
GERP RS		3.0
Varity_R		0.044
gMVP		0.16
Mutation Taster		=96/4	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: rs137966135; hg19: chr18-32954082;