Genetic Variant ZFAND2A:p.Lys50Arg (chr7-1157657-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_182491.4(ZFAND2A):c.149A>G(p.Lys50Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000253 in 1,425,662 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000025 ( 3 hom. )

Consequence

ZFAND2A
NM_182491.4 missense, splice_region

Scores

Splicing: ADA: 0.9994

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.13

Variant links:

Genes affected

ZFAND2A (HGNC:28073): (zinc finger AN1-type containing 2A) Predicted to enable zinc ion binding activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process and protein targeting to ER. Predicted to act upstream of or within cellular response to arsenic-containing substance and positive regulation of proteasomal ubiquitin-dependent protein catabolic process. Predicted to be located in nucleus. Predicted to be part of proteasome complex. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ZFAND2A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAND2A	NM_182491.4 link	c.149A>G	p.Lys50Arg	missense_variant, splice_region_variant	Exon 3 of 5	ENST00000316495.8	NP_872297.2	Q8N6M9
ZFAND2A	NM_001365383.1 link	c.149A>G	p.Lys50Arg	missense_variant, splice_region_variant	Exon 3 of 6		NP_001352312.1
ZFAND2A	NM_001365381.2 link	c.149A>G	p.Lys50Arg	missense_variant, splice_region_variant	Exon 3 of 5		NP_001352310.1
ZFAND2A	NR_158186.2 link	n.427A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFAND2A	ENST00000316495.8 link	c.149A>G	p.Lys50Arg	missense_variant, splice_region_variant	Exon 3 of 5	1	NM_182491.4	ENSP00000314619.3		Q8N6M9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000909

AC:

AN:

220082

Hom.:

AF XY:

0.0000167

AC XY:

AN XY:

120068

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1425662

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

707724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000364

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149A>G (p.K50R) alteration is located in exon 3 (coding exon 2) of the ZFAND2A gene. This alteration results from a A to G substitution at nucleotide position 149, causing the lysine (K) at amino acid position 50 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

Benign

0.094

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

T;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.5

.;.;M

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.021

D;D;T

Sift4G

Benign

0.10

T;.;T

Polyphen

0.77, 0.96

.;P;D

Vest4

0.62

MutPred

0.39

Loss of ubiquitination at K50 (P = 0.0155);Loss of ubiquitination at K50 (P = 0.0155);Loss of ubiquitination at K50 (P = 0.0155);

MVP

0.30

MPC

0.055

ClinPred

0.86

GERP RS

5.0

Varity_R

0.46

gMVP

0.068

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.48

Position offset: -1

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