Genetic Variant ZFP69B:p.Leu110Arg (chr1-40457060-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_023070.3(ZFP69B):c.329T>G(p.Leu110Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000312 in 1,603,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ZFP69B
NM_023070.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67

Variant links:

Genes affected

ZFP69B (HGNC:28053): (ZFP69 zinc finger protein B) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in Golgi organization. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ZFP69B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP69B	NM_023070.3 link	c.329T>G	p.Leu110Arg	missense_variant	Exon 3 of 5	ENST00000361584.5	NP_075558.2	Q9UJL9-1
ZFP69B	NM_001369565.1 link	c.329T>G	p.Leu110Arg	missense_variant	Exon 4 of 6		NP_001356494.1
ZFP69B	XM_005271136.2 link	c.329T>G	p.Leu110Arg	missense_variant	Exon 4 of 6		XP_005271193.1
ZFP69B	XM_017002147.2 link	c.329T>G	p.Leu110Arg	missense_variant	Exon 4 of 6		XP_016857636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZFP69B	ENST00000361584.5 link	c.329T>G	p.Leu110Arg	missense_variant	Exon 3 of 5	1	NM_023070.3	ENSP00000354547.4	Q9UJL9-1
ZFP69B	ENST00000484445.5 link	c.243T>G	p.Pro81Pro	synonymous_variant	Exon 3 of 5	1		ENSP00000435907.1	E9PS66
ZFP69B	ENST00000411995.6 link	c.329T>G	p.Leu110Arg	missense_variant	Exon 4 of 6	5		ENSP00000399664.2	Q9UJL9-1
ZFP69B	ENST00000469416.1 link	n.709T>G		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

239122

Hom.:

AF XY:

0.00000773

AC XY:

AN XY:

129370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000950

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451294

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721674

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.0000711

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.329T>G (p.L110R) alteration is located in exon 3 (coding exon 3) of the ZFP69B gene. This alteration results from a T to G substitution at nucleotide position 329, causing the leucine (L) at amino acid position 110 to be replaced by an arginine (R). 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

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.66

.;T

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

4.9

H;H

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.2

D;.

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.84

Gain of MoRF binding (P = 0.0673);Gain of MoRF binding (P = 0.0673);

MVP

0.21

MPC

0.59

ClinPred

0.99

GERP RS

3.3

Varity_R

0.92

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over