17-4049808-A-G

Position:

• chr17-4049808-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015113.4(ZZEF1):​c.5915T>C​(p.Leu1972Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,240 control chromosomes in the GnomAD database, including 139,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.49 (20908 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118169 hom.)
• Consequence: ZZEF1 NM_015113.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64

Genes affected

ZZEF1 (HGNC:29027): (zinc finger ZZ-type and EF-hand domain containing 1) Predicted to enable ubiquitin-like protein ligase activity. Predicted to act upstream of or within several processes, including glutamatergic synaptic transmission; regulation of peptidyl-tyrosine phosphorylation; and visual learning. Predicted to be located in cell surface; postsynapse; and presynaptic active zone. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.865237E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZZEF1	NM_015113.4	c.5915T>C	p.Leu1972Pro	missense_variant	37/55	ENST00000381638.7	NP_055928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZZEF1	ENST00000381638.7	c.5915T>C	p.Leu1972Pro	missense_variant	37/55	1	NM_015113.4	ENSP00000371051	P1
ZZEF1	ENST00000571436.5	c.*583T>C		3_prime_UTR_variant, NMD_transcript_variant	8/15	1		ENSP00000459023
ZZEF1	ENST00000573183.1	c.1079T>C	p.Leu360Pro	missense_variant	8/15	2		ENSP00000458554
ZZEF1	ENST00000572426.5	n.2073T>C		non_coding_transcript_exon_variant	12/15	2

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74931 AN: 151972 Hom.: 20848 Cov.: 32

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.461

GnomAD3 exomes AF: 0.406 AC: 101844 AN: 251110 Hom.: 22312 AF XY: 0.399 AC XY: 54215 AN XY: 135712

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.251

Gnomad SAS exome AF: 0.374

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.395 AC: 577827 AN: 1461150 Hom.: 118169 Cov.: 44 AF XY: 0.394 AC XY: 286617 AN XY: 726858

Gnomad4 AFR exome AF: 0.795

Gnomad4 AMR exome AF: 0.428

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.377

Gnomad4 FIN exome AF: 0.379

Gnomad4 NFE exome AF: 0.388

Gnomad4 OTH exome AF: 0.403

GnomAD4 genome AF: 0.493 AC: 75053 AN: 152090 Hom.: 20908 Cov.: 32 AF XY: 0.488 AC XY: 36278 AN XY: 74366

Gnomad4 AFR AF: 0.774

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.362

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.461

Alfa AF: 0.405 Hom.: 32378

Bravo AF: 0.513

TwinsUK AF: 0.375 AC: 1391

ALSPAC AF: 0.390 AC: 1502

ESP6500AA AF: 0.758 AC: 3341

ESP6500EA AF: 0.393 AC: 3384

ExAC AF: 0.413 AC: 50157

Asia WGS AF: 0.354 AC: 1231 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.400

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.0
DANN	Benign	0.64
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.00082	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.15
Sift	Benign	0.22	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.25
ClinPred		0.0080	T
GERP RS		5.5
Varity_R		0.061
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs781852; hg19: chr17-3953102; COSMIC: COSV67556011;