18-76878151-C-T

Position:

• chr18-76878151-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001306089.2(ZNF236):​c.983C>T​(p.Thr328Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,605,590 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: ZNF236 NM_001306089.2 missense, splice_region
• Scores: Splicing: ADA: 0.4525
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

Genes affected

ZNF236 (HGNC:13028): (zinc finger protein 236) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in cellular response to glucose stimulus. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031701267).
• BS2: High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF236	NM_001306089.2	c.983C>T	p.Thr328Met	missense_variant, splice_region_variant	7/31	ENST00000320610.14	NP_001293018.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF236	ENST00000320610.14	c.983C>T	p.Thr328Met	missense_variant, splice_region_variant	7/31	1	NM_001306089.2	ENSP00000322361	P1
ZNF236	ENST00000253159.12	c.977C>T	p.Thr326Met	missense_variant, splice_region_variant	7/31	1		ENSP00000253159
ZNF236	ENST00000543926.6	c.977C>T	p.Thr326Met	missense_variant, splice_region_variant, NMD_transcript_variant	7/32	1		ENSP00000444524
ZNF236	ENST00000579322.1	n.1255C>T		splice_region_variant, non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 114 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000749 AC: 184 AN: 245792 Hom.: 0 AF XY: 0.000675 AC XY: 90 AN XY: 133342

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.00127 AC: 1843 AN: 1453372 Hom.: 2 Cov.: 30 AF XY: 0.00117 AC XY: 849 AN XY: 722684

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000734

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00130

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.000950

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000712 AC XY: 53 AN XY: 74424

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000676

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000274 AC: 1

ESP6500EA AF: 0.000735 AC: 6

ExAC AF: 0.000704 AC: 85

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

Jan 11, 2023

The c.977C>T (p.T326M) alteration is located in exon 7 (coding exon 7) of the ZNF236 gene. This alteration results from a C to T substitution at nucleotide position 977, causing the threonine (T) at amino acid position 326 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.071
Sift	Uncertain	0.0060	D;D;.
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.97	.;D;.
Vest4		0.10
MVP		0.30
MPC		0.69
ClinPred		0.024	T
GERP RS		4.2
Varity_R		0.057
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.45
dbscSNV1_RF	Benign	0.37
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: rs200475993; hg19: chr18-74590107; COSMIC: COSV53491014; COSMIC: COSV53491014;