19-53576886-A-T

Position:

• chr19-53576886-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_001079906.2(ZNF331):​c.326A>T​(p.Lys109Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,130 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (47 hom.)
• Consequence: ZNF331 NM_001079906.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.989

Genes affected

ZNF331 (HGNC:15489): (zinc finger protein 331) This gene encodes a zinc finger protein containing a KRAB (Kruppel-associated box) domain found in transcriptional repressors. This gene may be methylated and silenced in cancer cells. This gene is located within a differentially methylated region (DMR) and shows allele-specific expression in placenta. Alternative splicing and the use of alternative promoters results in multiple transcript variants encoding the same protein. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM1: In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity ZN331_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.007546127).
• BP6: Variant 19-53576886-A-T is Benign according to our data. Variant chr19-53576886-A-T is described in ClinVar as [Benign]. Clinvar id is 771042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF331	NM_001079906.2	c.326A>T	p.Lys109Ile	missense_variant	6/6	ENST00000449416.6	NP_001073375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF331	ENST00000449416.6	c.326A>T	p.Lys109Ile	missense_variant	6/6	5	NM_001079906.2	ENSP00000393817	P1

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 836 AN: 152168 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00830

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00665 AC: 1672 AN: 251390 Hom.: 10 AF XY: 0.00662 AC XY: 899 AN XY: 135868

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00786

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.00673 AC: 9842 AN: 1461844 Hom.: 47 Cov.: 30 AF XY: 0.00670 AC XY: 4869 AN XY: 727222

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00624

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00369

Gnomad4 FIN exome AF: 0.00947

Gnomad4 NFE exome AF: 0.00742

Gnomad4 OTH exome AF: 0.00621

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152286 Hom.: 4 Cov.: 33 AF XY: 0.00521 AC XY: 388 AN XY: 74454

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00830

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00690 Hom.: 2

Bravo AF: 0.00522

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00771 AC: 936

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 01, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.26	.;.;.;.;T;.;.;.;.;.;.;T;.;.;.
MetaRNN	Benign	0.0075	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;L;L;L;L;L;L;L;.;.;L;L;L
MutationTaster	Benign	0.99	D;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.0	.;D;.;D;D;D;D;.;D;D;D;D;.;.;.
REVEL	Benign	0.079
Sift	Uncertain	0.023	.;D;.;D;D;D;D;.;D;D;D;D;.;.;.
Sift4G	Benign	0.070	.;T;.;T;T;T;T;.;T;T;D;D;.;.;.
Polyphen		0.045	B;B;B;B;B;B;B;B;B;B;.;.;B;B;B
Vest4		0.27, 0.34, 0.31, 0.33, 0.28, 0.30, 0.28
MVP		0.47
MPC		1.4
ClinPred		0.014	T
GERP RS		2.6
Varity_R		0.24
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112855712; hg19: chr19-54080140;