19-30548762-C-T

Variant names:

• chr19-30548762-C-T
• rs77238711
• NM_014717.3:c.3143C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014717.3(ZNF536):​c.3143C>T​(p.Ala1048Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,832 control chromosomes in the GnomAD database, including 1,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (135 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1373 hom.)
• Consequence: ZNF536 NM_014717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0720

Genes affected

ZNF536 (HGNC:29025): (zinc finger protein 536) The protein encoded by this gene is a highly conserved zinc finger protein. The encoded protein is most abundant in brain, where it negatively regulates neuronal differentiation. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017009676).
• BP6: Variant 19-30548762-C-T is Benign according to our data. Variant chr19-30548762-C-T is described in ClinVar as [Benign]. Clinvar id is 403626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF536	NM_014717.3	c.3143C>T	p.Ala1048Val	missense_variant	Exon 4 of 5	ENST00000355537.4	NP_055532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF536	ENST00000355537.4	c.3143C>T	p.Ala1048Val	missense_variant	Exon 4 of 5	1	NM_014717.3	ENSP00000347730.1

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5024 AN: 152096 Hom.: 135 Cov.: 33

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00368

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0364 AC: 9128 AN: 251030 Hom.: 295 AF XY: 0.0401 AC XY: 5446 AN XY: 135664

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.0321

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0361 AC: 52831 AN: 1461618 Hom.: 1373 Cov.: 33 AF XY: 0.0382 AC XY: 27804 AN XY: 727084

Gnomad4 AFR exome AF: 0.0319

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0330 AC: 5024 AN: 152214 Hom.: 135 Cov.: 33 AF XY: 0.0338 AC XY: 2512 AN XY: 74422

Gnomad4 AFR AF: 0.0314

Gnomad4 AMR AF: 0.0227

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00349

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0299 Hom.: 125

Bravo AF: 0.0297

TwinsUK AF: 0.0324 AC: 120

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.0365 AC: 161

ESP6500EA AF: 0.0335 AC: 288

ExAC AF: 0.0383 AC: 4653

Asia WGS AF: 0.0600 AC: 208 AN: 3478

EpiCase AF: 0.0322

EpiControl AF: 0.0317

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.7
DANN	Benign	0.89
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.025
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.022
MPC		0.12
ClinPred		0.0026	T
GERP RS		0.61
Varity_R		0.025
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs77238711; hg19: chr19-31039669; COSMIC: COSV62835849; COSMIC: COSV62835849;